Season Premiere. Three weeks after the death of Derek Fossen, Greene faces interrogation at an M&M conference. However, Corday is the only one to suspect something wrong. Meanwhile, Carter's parents return to town for his grandfather's funeral, which Abby briefly attends. Abby has decisions to make; Luka wants her to move in with him. Weaver returns from an impromptu vacation, worried that Romano has outed her to the staff. Chen is the new chief resident. Benton deals with Cleo's meds and Jackie's problems adjusting to life after Jesse's death. The ER is filled with patients after a brawl at a talk show taping. Legaspi got a job in San Francisco.
After finishing a shift, Carter approaches Weaver about an attending position, and then gets sucked back into work when a stampede at a rock concert brings in many patients. Abby and Luka break up. When Weaver goes MIA, Malucci and Chen make a severe mistake with a patient, ultimately leading to the patient's death. They blame it on Weaver for not answering their pages; we later see that Weaver left her pager in the bathroom at Doc Magoo's. Carla and Reese get into a car accident, which kills Carla and injures Reese. Mark and Elizabeth struggle to balance parenthood and their schedules.
Malucci and a female paramedic become trapped in an elevator with a man who is vomiting blood. Malucci saves the man's life and celebrates by having sex with the paramedic in an ambulance, which ultimately results in his dismissal by Weaver. Abby move's out of Luka's apartment and accidentally breaks his fish tank on the way out. Chen treats an abandoned infant with a birthmark in the shape of the sign of the Virgin Mary. Meanwhile, the strain of motherhood may be catching up with Corday when she falls asleep during surgery.
Susan Lewis arrives in Chicago to interview around town and have lunch with Mark. She gets reacquainted with the nurses and Carter, meets Elizabeth, and is later offered an attending position by Mark. Weaver and Chen clash over a risk management meeting, and ultimately, Chen quits. Mark and Elizabeth treat a six-year-old Edwards Syndrome patient whose parents abandon him while he is in surgery. When Benton becomes stuck in surgery he must resort to calling Roger to pick up Reese.
Weaver prepares to call her birth mother, while she treats a man who was accidentally run over by his daughter while she was drunk. Susan's first day back is typically hectic, as she treats a girl with an ectopic pregnancy who refuses to stay for treatment and a man faking a coma to escape his bookie. Abby seems to notice the chemistry between Susan and Carter and gets a little jealous. Cleo has gotten a better job 40 minutes outside of Chicago. The Greene household is pretty crazy now that Rachel is living there. After Elizabeth loses another patient to a post-op infection, an investigation is launched and someone is assigned to shadow her all day to check her cleanliness. Benton panics when Roger reveals that he can't find Reese--it turns out that Jackie picked him up from school after he got in a fight. Carter's day as chief resident is marred a little when his grandmother comes to the ER after slipping.
Susan and Carter attend a yoga class before work. At work, they discover an outbreak of meningococcus. Abby discovers that Luka had Nicole hired as a runner, even though she doesn't know what she's doing, and flirts with a fireman with a broken leg. Carter and Abby discuss their relationship. Corday continues to be shadowed by Infection Control and looks for a pattern after her fourth post-op sepsis death. She discovers that an official investigation has been launched into her being an "angel of mercy" and the police will be contacting her. Corday also fights with Rachel upon discovering Ella unattended. Benton tells Roger that he doesn't want him having any more contact with Reese. Luka treats a young man using his portable catheter for heroin injection. Benton and Abby treat a kid who tried self circumcision to please his girlfriend.
A new med student assigned to Carter finds all sorts of surprises in store for him on his first day. Elizabeth spends her day searching for the angel of death, finding that all signs point towards Dr. Babcock. Nicole has a rough day training to become a nurse's aide, and draws Abby's ire after Luka invites her into a trauma. Puzzled by his grandmother's fainting spells, Carter discovers that she is at great risk for a heart attack or stroke. He and Susan treat a law student/med student who has been cutting herself. The two grow closer, as Carter finally tells her about his stabbing and drug addiction. Mark picks up Rachel at school after she's suspended. Peter is sued by Roger for custody and takes a DNA test to determine whether he is Reese's real father. Despondent over badly injuring a young skateboarder, a mall security guard tries to hang himself.
An enormous rainstorm pelts Chicago. Cleo's last day at County is interrupted by the arrival of Benton's DNA results: he's not Reese's biological father. Benton meets with his lawyer regarding the trial; she advises him to let Roger see Reese; he refuses. Money from the nurses' secret stash and Frank's Palm Pilot go missing, only to turn up in Nicole's purse. She later tells Luka that she's pregnant. Susan accuses Mark of being grumpy with his patients; he spends the day treating a kid who fell in the river with his younger brother and whose parents blame him. Weaver travels to an accident site, where Pickman's ambulance was rammed by an SUV. She treats a pregnant stab wound, going as far as to give her a C-section in the broken ambulance, with Gallant's help. Weaver interracts with paramedic Sandy Lopez for the first time at the accident scene. Carter's grandmother comes in after being involved in a hit-and-run and breaking her hip. She becomes delusional in an MRI machine, calling out for her husband.
Susan and Carter get together after treating a newlywed couple where the wife may have an unusual allergy. Weaver asks firefighter Sandy Lopez out. Mark and Gallant treat members of a boxing family. Rachel's boyfriend is admitted with a broken ankle and tests positive for marijuana. Elizabeth tends to a comatose woman whose husband will only agree to a risky procedure to harvest her organs. Abby openly questions Nicole's pregnancy and Nicole makes a confession to Luka. Benton's custody trial for Reese is hampered by his long hours.
Benton commits perjury on the witness stand in order to gain custody of Reese. When Romano refuses to give him a more even schedule, Peter resigns and seeks a job at the clinic where Cleo is newly employed. Benton is granted custody of Reese and he and Cleo decide to move to the suburbs together. Carter's father visits for Christmas with the news that he's getting divorced. Weaver and Sandy Lopez finally go on a date. Abby catches Nicole in the maternity ward, recovering from an abortion.
Abby has a horrible birthday, beginning with meeting her new squabbling neighbors. She treats a young woman hoping to get pregnant by taking fertility drugs, and discovers that Luka is going to Bosnia for two months as part of the Doctors Without Borders program. Her ex-husband tells her that he's getting remarried just before she sees Carter and Susan sharing a private moment. She takes care of a young boy abandoned in the ER after the death of his mother. Paul Sobricki is admitted with a head lac, and Abby unsuccessfully tries to keep Carter from seeing him. Abby's day ends with her sharing a beer with her neighbor. Carter has problems of his own: his mother is back in town, just getting in the way and refusing to admit to her mistakes. He also meets with Chen, who reveals that she has the evidence to take Weaver down in the Marfan's case. Weaver and Lopez are an item until Sandy discovers that Weaver has not come out at work. Mark finds cigarettes and condoms in Rachel's room.
Chen returns to the hospital with proof of Weaver's misplaced pager and demands her job back, threatening a lawsuit. Weaver disapproves of the idea, but Romano forces her to do it. As her colleagues watch, Sandy Lopez plants a kiss on Weaver, effectively outing her. Carter attempts to mediate between his bickering parents. Mark and Elizabeth's opinions on Rachel's future differ, but Mark decides to keep her in Chicago for the time being. Abby attempts to mediate between her fighting neighbors after Brian beats up Joyce. Lewis treats a death row inmate who wants a DNR order.
Eleanor Carter tends to a young leukemia patient, trying to make up for Bobby's death many years ago. Mark treats the victims of a letter bomb, and later treats his own daughter when Ella is rushed in after swallowing some of Rachel's Ecstasy. Abby treats a young girl who has been chauffering her drunken mother around. Abby also hides Joyce in her apartment while Brian searches for her and causes a ruckus. An allergic Gallant treats a blind man with a dog. Chen returns to the day shift, working with Weaver for the first time. Romano gives some of Weaver's duties to Lewis, making Kerry mad, until she meets a new friend on her way home.
The ER faces a staff shortage when several employees are sent home with food poisoning, including Weaver. Mark and Elizabeth's marriage is in crisis following Ella's hospital admission. Adding to his woes, Mark fears his brain tumor may have returned. Eleanor Carter nearly abandons young Mickey after realizing how bad his condition is. Abby pays the price to protect Joyce from her unhappy husband, Brian, when she is punched by him. Luka later tracks down Brian and threatens to hug him.
Mark learns that his tumor is back and inoperable, giving him 4-5 months to live. Corday is living in a hotel, and confesses to Benton that she thinks she's left Mark. Susan cares for Mark after his first radiation treatment. Abby learns that the case against Brian has been dropped because somebody beat him up. Seeing Brian enter her building, she seeks comfort at Luka's, where he's engaged in a game of Pictionary with his friends. Jerry and Frank clash, leading to a fistfight. Chen has a stalker.
An unusual patient trigger's the curiosity of Abby, Susan, Gallant, Luka and Carter, which lands them at an all-day sexual harassment seminar. Throughout the day, Carter and Luka clash, Abby and Susan bond, and everyone discovers something new about each other. Susan breaks it off with Carter when she realizes his feelings for Abby, while news and gossip spreads through the ER of Elizabeth and Mark's separation.
Corday, still living in the hotel, is avoiding Mark, until Ella says her first words. Elizabeth pressures Susan to tell her what her husband is hiding, and figures out her husband's fate. Romano advises her to return to Mark for the little time he has left. Chen treats a man too traumatized to speak. Mark tells the staff about his prognosis. Weaver worries about Sandy Lopez as she is reported missing in a fire. Weaver tracks her down at a bar, and the two make out. Stabbings on a college campus bring girls to the ER.
Mark serves his final day in the ER overseeing the first day of Gregory Pratt, a cocky yet eager new intern. Through observing his patients, he decides to forego chemotherapy, and spend his remaining days in peace. He also meets with his ex-wife, tells Weaver to live a little and leaves, never to return. Meanwhile, Abby plans to move back into her apartment when her landlord lets her know that Brian's moved out.
Susan receives a message from her niece on her answering machine, saying that Chloe's "sick." The call is traced to New York City, putting Susan on a plane. Officers Boscorelli and Yokas are assigned to chaperone Susan in the search for her sister. Chloe is found in "Urinetown," suffering a broken heart, but Little Susie is not with her. Pratt hits on Chen several times throughout the day, and also performs an unauthorized procedure with Gallant on a dying man. Abby returns to her apartment, where Carter catches her drinking a beer. He confronts Luka about her relapse, and Abby herself later. She tells Carter not to worry about her. Romano signs Weaver up to meet with the Women's Health Coalition. Corday requests immediate time off from Romano to join Mark and Rachel in Hawaii.
A letter from Dr. Greene arrives via fax, and Carter reads it to the staff. Everybody is stunned when he reaches the last page, a note from Dr. Corday, stating that Mark died that morning. Frank posts the letter and various staff members who weren't in attendance take time to read it. Sandy gets Weaver to admit that she's lost a friend. Luka, Abby, Haleh, Susan and Gallant are joined by Weaver and Sandy at a bar. Carter comes looking for Abby and they end up talking all night at Doc Magoo's. Abby goes to an AA meeting later that day, and tells Carter that she went for him. Carter takes his place as the rock of the ER. Meanwhile, Susan learns that Chloe is in rehab and Suzie is staying with Joe, Pratt matches County, and Romano operates on a girl with a genetic deficiency.
Mark decides to use his remaining time to help "fix" Rachel; he takes her to Hawaii to show her where he grew up. He teaches her how to surf and how to drive a stick shift. He catches her chasing one of his Percocet with a shot of vodka and confronts her about wasting her life. One day after surfing he has a seizure, and Rachel contacts Elizabeth, who soon arrives with little Ella. Elizabeth wants to take Mark home, but he refuses. Very early one morning, he dies. After the funeral, Rachel tells Elizabeth she'd like to visit Ella, and Elizabeth agrees.
Season Finale. The day begins slowly as Weaver calls to say she'll be late, and Chen thinks she's developing a fever. Then multiple MVAs come in, quickly followed by two children suffering what appears to be smallpox. The staff panics, but not as bad as the patients, when a lockdown is ordered for the ER. The feverish Chen is quarantined with homeless Stan. Lewis takes charge as Weaver arrives and the police won't let her in. The girl infected by smallpox dies and Pratt embarasses Carter in front of her parents. Carter notices Pratt is sick as well, and sends him to Chen's room. Jerry phones the news, and the patients riot, nearly using a gurney to break open the emergency bay doors. Control of the ER is relieved from Weaver by an infection specialist. The staff prepares to stay, still not having a confirmation on whether it is smallpox or not, and the lockdown continuing as a result. Carter and Abby kiss after being quarantined together.