Ramis, 69, died early Monday morning of complications from vasculitis, which causes inflammation and damage to blood vessels, said Chris Day, a spokesman at United Talent Agency. Ramis was surrounded by family and friends.
Ramis was a key factor in some of the biggest blockbuster comedies in the 1970s and 1980s.
He co-wrote "Animal House," which starred fellow Second City alum John Belushi. He teamed up with Second City alums Bill Murray and Dan Aykroyd on "Ghostbusters," in which Ramis co-starred and helped write. He also co-wrote "Meatballs" and "Caddy Shack," both of which starred Murray.
"The best comedy touches something that's timeless and universal in people," Ramis told The Associated Press in a 2009 story about the 50th anniversary of Second City. "When you hit it right, those things last."
More recently, he directed "Analyze This," starring Billy Crystal and Robert DeNiro.
Aykroyd issued a statement Monday, saying he was "deeply saddened to hear of the passing of my brilliant, gifted, funny friend ... May he now get the answers he was always seeking."
Ramis was born Nov. 21, 1944 in Chicago. He is survived by his wife, Erica Ramos; sons Julian and Daniel; daughter, Violet, and two grandchildren.
Associated Press writers Don Babwin in Chicago, Jake Coyle in New York and Steve Loeper in Los Angeles contributed to this report.