| •Noah Wyle | played | Dr. John Carter (episodes 1-246, recurring otherwise) |
| •Goran Visnjic | played | Dr. Luka Kovac (episodes 115-291) |
| •Maura Tierney | played | Dr. Abby Lockhart (episodes 126+, recurring previously) |
| •Mekhi Phifer | played | Dr. Gregory Pratt (episodes 181+, recurring previously) |
| •Parminder Nagra | played | Dr. Neela Rasgotra (episodes 205+, recurring previously) |
| •John Stamos | played | Tony Gates (episodes 270+, recurring previously) |
| •Linda Cardellini | played | Nurse Samantha Taggart (episodes 208+, recurring previously) |
| •Shane West | played | Dr. Ray Barnett (episodes 225-291) |
| •Scott Grimes | played | Dr. Archie Morris (episodes 247+, recurring previously) |
| •Laura Innes | played | Dr. Kerry Weaver (episodes 49-291, recurring otherwise) |
| •Sherry Stringfield | played | Dr. Susan Lewis (episodes 1-56, 162-247) |
| •Ming-Na | played | Dr. Jing-Mei "Deb" Chen (episodes 124-233, recurring previously) |
| •Alex Kingston | played | Dr. Elizabeth Corday (episodes 71-228) |
| •Sharif Atkins | played | Dr. Michael Gallant (episodes 173-220, recurring otherwise) |
| •Paul McCrane | played | Dr. Robert Romano (episodes 115-210, recurring previously) |
| •Anthony Edwards (1) | played | Dr. Mark Greene (episodes 1-180) |
| •Eriq La Salle (1) | played | Dr. Peter Benton (episodes 1-168, 173, 179) |
| •Michael Michele | played | Dr. Cleo Finch (episodes 115-168, 179) |
| •Erik Palladino | played | Dr. Dave Malucci (episodes 121-162, recurring previously) |
| •Julianna Margulies | played | Nurse Carol Hathaway (episodes 3-135, recurring previously) |
| •Kellie Martin | played | Lucy Knight (episodes 93-128) |
| •Gloria Reuben | played | Nurse Jeanie Boulet (episodes 32-120, recurring previously) |
| •George Clooney | played | Dr. Doug Ross (episodes 1-107) |
| •Maria Bello | played | Dr. Anna Del Amico (episodes 71-92, recurring previously) |
