The original starring cast consisted of Anthony Edwards as Dr. Mark Greene, George Clooney as Dr. Douglas "Doug" Ross, Sherry Stringfield as Dr. Susan Lewis, Noah Wyle as medical student (later Dr.) John Carter, and Eriq La Salle as Dr. Peter Benton.
Notably, of the 26 main cast members that starred throughout ER's 15-season run, only seven were not featured in the final season: Gloria Reuben, Maria Bello, Kellie Martin, Michael Michele, Erik Palladino, Ming-Na, and Sharif Atkins.
In addition, only four main cast members never made a return appearance of any type following their original stint: Maria Bello, Kellie Martin, Erik Palladino, and Mekhi Phifer.
George Clooney left the show in the Season 5 episode "The Storm (Part II)," when his character, Doug Ross, resigned before being fired for his involvement in a patient's death.
Gloria Reuben departed early in Season 6, in the episode "The Peace of Wild Things," when her character, Jeanie Boulet, decided to become a stay-at-home mom and care for her newly adopted HIV-positive baby.
Kellie Martin, who played medical student Lucy Knight, left the series midway through Season 6 in the episode "All in The Family," when her character was killed by a patient with undiagnosed schizophrenia; his psychotic break occurred before a backed-up psychiatry department could arrive in the ER for a consult.
Julianna Margulies left the show at the end of Season 6, in the episode "Such Sweet Sorrow," when her character, Carol Hathaway, decided on the spur of the moment to go to Seattle, Washington, and reunite with Doug Ross, her true love and the father of her twin daughters.
He took a job with a set schedule at another hospital in order to spend more time with his son, Reese, and his girlfriend, former fellow ER doctor Cleo Finch.
Edwards returned in the Season 15 episode "Heal Thyself" where he appeared in multiple flashback scenes to give insight into the past of Angela Bassett's character.
Alex Kingston's character, Elizabeth Corday, departed early in Season 11 in the episode "Fear" after getting in trouble for performing an illegal organ donation procedure; rather than being summarily fired, County offered her a demotion to a non-tenured position, but she turned it down and opted to return to England instead.
Ming-Na departed midway through Season 11 in the episode "Twas The Night" when her character, Jing-Mei Chen, resigned in order to take care of her ailing father, whom she later euthanized.
Laura Innes left midway through Season 13 in the episode "A House Divided," when a reluctant Luka Kovač was forced by budget cuts to fire her character, Kerry Weaver due to her high salary.
After bracing for a battle to keep her position, and in spite of the fact that Kovač realized he must find a way to keep her on staff, Weaver ultimately decided to resign from County and accept a job offer from a television station in Miami, Florida.
Shane West left in the Season 13 finale, "The Honeymoon Is Over," after his character, Ray Barnett got hit by a truck, lost both his legs and returned to Baton Rouge with his mother to recuperate.
Mekhi Phifer departed in the Season 15 premiere, "Life After Death," when his character, Greg Pratt, died in the ER as the result of blast injuries suffered in an ambulance explosion.