Margulies, who played nurse Carol Hathaway on the NBC hospital drama from its 1994 premiere, exited after six seasons. Her character left Chicago's County General for Seattle, settling down with Dr. Doug Ross, who had been played by George Clooney.
"I feel like I left Carol Hathaway in the best scenario possible," Margulies said Saturday, laying to rest speculation about her return. "I can't imagine making it any better than that."
In the farewell lap of its 15-season run, "ER" last week featured Anthony Edwards reprising his role of Dr. Mark Greene. NBC has announced upcoming appearances by fellow alums Noah Wyle and Eriq La Salle, who will also direct an episode.
Still a mystery is whether Clooney, yet another charter cast-member, will be back. He left in 1999.
Margulies, 42, departed from the Los Angeles-based series in 2000 despite a reported offer of $27 million to stay for three more seasons. She expressed a wish to return home to New York and pursue other projects.
She has appeared in a number of films and TV shows, including a memorable guest role as a real estate agent with a heroin habit on "The Sopranos." Last spring she starred in the short-lived Fox legal drama "Canterbury's Law."
Margulies lives in Manhattan with attorney husband Keith Lieberthal and their son Kieran, who was born in January.
She recently finished shooting "City Island," a comedy that also stars Andy Garcia, Alan Arkin and Emily Mortimer.