Clooney can currently be seen in Coen brothers comedy Burn After Reading
The producers of ER are "optimistic" about persuading George Clooney to appear in the hospital drama's final season, according to reports.
"We have a really good storyline for every character from the past," said executive producer David Zabel in an interview with US magazine TV Guide.
Former cast members Anthony Edwards and Noah Wyle have agreed to return for the long-running show's last series.
Clooney's spokesman, though, reiterated earlier denials of an ER comeback.
"He is on record as saying he is not coming back," said Stan Rosenfield. "It is something he has already done."
Set in the emergency room of the fictional Chicago-based County General Hospital, ER was the top-rated drama on US television for several years.
The series will end with a two-hour finale in May 2009, preceded by a one-hour retrospective.
Edwards - whose character, Dr Mark Greene, died in 2002 - will appear in flashback form in an episode called Heal Thyself.
Wyle, meanwhile, is due to appear in four episodes as Dr John Carter.
Clooney, who shot to fame as Dr Doug Ross, left the show in 1999 but made a surprise cameo the following year.
According to his publicist, however, the 47-year-old actor is now "busy making movies".