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Marcia Gay Harden as Dr. Leanne Rorish, an ER attending physician, known to current and former resident doctors as "Daddy". Her husband and two children were killed after their car was hit by a drunk driver; this sometimes influences her medical decisions. Originally the ER's Residency Director, Leanne is promoted to Director of Emergency Medicine. She is replaced in this position by Dr. Campbell in "Second Year". In "Fallen Angels", Leanne is shown to have taken guardianship of a young orphan.
Raza Jaffrey as Dr. Neal Hudson, an ER attending physician. A British-Indian former surgeon, his approach is quieter and more people-oriented, than his mentor Dr. Rorish. He connected with Christa during her first year of residency. In "Hail Mary", Hudson becomes a surgical attending, and is once again assigned to the ER (season 1).
Bonnie Somerville as Dr. Christa Lorenson, a mature first-year resident. She was married with a son who died of brain cancer. Her experience and her divorce inspired her to attend medical school (season 1).
Melanie Chandra as Dr. Malaya Pineda, a first-year resident (seasons 1–2). She went to medical school and did her internship at Angels Memorial, and is more familiar with the ER. She is a lesbian, who was once involved with a resident when she was a medical student.
William Allen Young as Dr. Rollie Guthrie, an ER attending physician with a very nurturing style; he takes Angus under his wing in his first days in the ER. Guthrie's wife committed suicide, a death that strained his relationship with his son, a surgeon. During season 2, Guthrie is diagnosed with Parkinson's disease, and undergoes corrective neurological surgery to delay the onset of symptoms. Guthrie had a daughter who died from carbon monoxide poisoning while Guthrie tried to save his son from a similar death.
Harry Ford as Dr. Angus Leighton, a first-year resident. His father is on the hospital board. He feels overshadowed by that and by the achievements of his older brother, a former resident, but slowly grows in confidence. In his third year he is encouraged to transfer and become a surgical resident.
Benjamin Hollingsworth as Dr. Mario Savetti, a first-year resident. He grew up poor and sees emergency medicine as his way out. He worked as a bartender before medical school.
Luis Guzmán as Jesse Salander, known as "Mama". A senior nurse who manages the residents, Jesse is tough but caring and supportive of the students. He and Dr. Rorish have a long-term, close friendship.
Boris Kodjoe as Dr. Will Campbell, Chief of Surgery. In season 2 he is assigned as the new Chief of the combined Surgery and Emergency medicine department in order to save costs, causing strife between him and Rorish. Campbell has a disabled daughter (season 2–3; recurring in season 1).
Jillian Murray as Dr. Heather Pinkney, a surgical resident who becomes involved with Mario.(season 2; recurring in season 1). He quickly ends it when he hears about her side relationship with Dr. Campbell. She gets in further trouble when it's revealed she's providing Angus with Adderall. When confronted by Campbell, she threatens to turn their past relationship into a sexual harassment case.
Rob Lowe as Dr. Ethan Willis, an Army Medical Corps colonel attached to the prestigious Combat Casualty Care research program. He joins the ER staff at Angels Memorial for the remainder of his service contract after the Army pulls him from the battlefield in Afghanistan. Willis brings with him revolutionary military medical techniques, and builds a strong friendship with Dr. Rorish (seasons 2–3).
Noah Gray-Cabey as Elliot Dixon, a first-year resident in the ER (season 2-3).
Emily Tyra as Noa Kean, an ER resident and former dancer. She begins a relationship with Dr. Mario Savetti (season 3; recurring season 2)
Emily Alyn Lind as Ariel Braeden (season 3; guest seasons 1–2)
Moon Bloodgood as Rox Valenzuela, a Los Angeles Fire Department paramedic. Rox is Ethan's ride-along partner (season 3).
