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His best known role to date is as Dr. Mark Greene on the long-running TV series ER, where he resided from its premiere in 1994 to the end of the 8th season in 2002.

The series also afforded Edwards his first opportunity to direct.

Edwards's desire to pursue directing led to his request to be written out of the series, leading to his character's death from brain cancer.

He reportedly earned $ 35, 000, 000 for three seasons on ER, which made him one of the highest-paid television actors to date.

Anthony Edwards and his former co-star George Clooney were the ones who suggested doing an episode of ER live.

The fourth season premiere, " Ambush " was performed live twice with an East Coast and West Coast version.