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| •Noah Wyle | played | Dr. John Carter (Episodes 1-245, 325-328, 331, recurring otherwise) (251Eps.) |
| •Parminder Nagra | played | Dr. Neela Rasgotra (Episodes 204-331, recurring previously) (128Eps.) |
| •John Stamos | played | Dr. Tony Gates (Episodes 269-331, recurring previously) (63Eps.) |
| •Linda Cardellini | played | Nurse Samantha Taggart (Episodes 206-331, recurring previously) (125Eps.) |
| •Scott Grimes | played | Dr. Archie Morris (Episodes 246-331, recurring previously) (86Eps.) |
| •David Lyons | played | Dr. Simon Brenner (Season 15, recurring previously) (22Eps.) |
| •Angela Bassett | played | Dr. Cate Banfield (Season 15) (21Eps.) |
| •Anthony Edwards (1) | played | Dr. Mark Greene (Episodes 1-179, 316) (181Eps.) |
| •Goran Visnjic | played | Dr. Luka Kovac (Episodes 114–290, 295, 298–300, 304, 306, 309, 312) (178Eps.) |
| •Maura Tierney | played | Dr. Abby Lockhart (Episodes 125–310, 312, recurring otherwise) (187Eps.) |
| •George Clooney | played | Dr. Doug Ross (Episodes 1-106, 328) (108Eps.) |
| •Mekhi Phifer | played | Dr. Gregory Pratt (Episodes 180–310, recurring previously) (131Eps.) |
| •Julianna Margulies | played | Nurse Carol Hathaway (Episodes 2-134, 328, recurring otherwise) (135Eps.) |
| •Shane West | played | Dr. Ray Barnett (Episodes 224–290, recurring afterwards) (67Eps.) |
| •Alex Kingston | played | Dr. Elizabeth Corday (Episodes 70-227, 331, recurring otherwise) (159Eps.) |
| •Laura Innes | played | Dr. Kerry Weaver (Episodes 48–280, 331, recurring otherwise) (244Eps.) |
| •Sherry Stringfield | played | Dr. Susan Lewis (Episodes 1–55, 161–246, 331) (142Eps.) |
| •Ming-Na | played | Dr. Jing-Mei "Deb" Chen (Episodes 123-232, recurring previously) (110Eps.) |
| •Sharif Atkins | played | Dr. Michael Gallant (Episodes 172-219, recurring otherwise) (48Eps.) |
| •Paul McCrane | played | Dr. Robert Romano (Episodes 114–209, recurring otherwise) (96Eps.) |
| •Eriq La Salle | played | Dr. Peter Benton (Episodes 1–167, 172, 178, 328, 331) (172Eps.) |
| •Michael Michele | played | Dr. Cleo Finch (Episodes 114–167, 178) (55Eps.) |
| •Erik Palladino | played | Dr. Dave Malucci (Episodes 120-161, recurring previously) (42Eps.) |
| •Kellie Martin | played | Lucy Knight (Episodes 92-127) (36Eps.) |
| •Gloria Reuben | played | P.A. Jeanie Boulet (Episodes 31–119, recurring otherwise) (89Eps.) |
| •Maria Bello | played | Dr. Anna Del Amico (Episodes 70–91, recurring previously) (22Eps.) |
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