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Lucy Knight (Kellie Martin) and Carter develop a liking for each other. Carter was jealous when Lucy started going out with Dr. Dale Edson (Matthew Glave). Carter and Lucy kiss only once as he decides to break things off owing to her being a medical student. They continued to be friends, until her death in Season 6.
Physician Assistant Jeanie Boulet leaves to care for her HIV-positive child. Lucy Knight and John Carter are attacked and stabbed by a psychotic patient. The ER staff work to save Carter and Lucy. Despite everyone's best efforts, they are unable to save Lucy who succumbs to her wounds and dies.
That same day, Lucy's mother, Barbara Knight, arrives to clear out her locker. She eventually seeks Carter out and they spend the afternoon talking, with Mrs. Knight recounting how Lucy loved San Francisco but went to Chicago to practice medicine before she begins sobbing over her daughter's death as Carter watches silently and sadly.
Weaver becomes more aggressive and she accepts that she is a lesbian. Greene's final episode as a regular character is the 21st episode of Season 8. Benton and Finch also leave to make new changes in their lives. After Greene's death, many of the characters become affected, especially Carter who reads two letters to the staff.
Abby fills in as Carter's date for a Carter family function and sees her ex-husband there, later making sure to ruin his evening. Malucci treats a gay man who wants to contract HIV from his positive partner. Greene continues an abrupt personality change in the wake of his surgery. Weaver makes an appointment for a competency review for Greene.
For the first time John Carter becomes the central character and Noah Wyle receives star billing. The death of Mark Greene continues to affect his colleagues while a grieving Corday has left Chicago for England. She returns and a medical student raises eyebrows. The ER is still plagued by the smallpox disease at the beginning.
Carter treats a 16-year-old girl with kidney failure after taking a new drug to control her seizures. Carter's old medical student, George Henry, is the girl's doctor and is a paid consultant to the manufacturer. When things get worse, the father commits suicide so that he can give his daughter his remaining kidney.
This is the final episode with Noah Wyle (who plays Dr. John Carter) as a regular cast member, although he has several guest appearances in later episodes. This is Scott Grimes' final episode before becoming a regular cast member in season 12, playing character Archie Morris.