He was 63.
Keyes died of complications from acromegaly, a pituitary gland disorder, according to his manager, Phil Brock.
Brock, president and CEO of Studio Talent Group, said Keyes was "the consummate character actor" and a good man.
"He was a client for over 20 years, and as menacing as he looked in person, when you worked with him, the heart was so warm. He was this person who everyone just loved," Brock said. "It's one of the rare things in the entertainment world, you don't necessarily end up with a lot of friends, but he was a friend as well as just a wonderful actor."
Rob Zombie, who directed Keyes in "House of 1,000 Corpses," posted a tribute on Facebook
"I have just heard the terrible news that our friend Irwin Keyes has passed away. Irwin was a cool guy and a big part of the House of 1000 Corpses family. He will be missed by us all," he wrote.
With his beefy physique and rubbery face -- a look that lent itself to thugs, comic heavies and winking horror villains -- Keyes, a New York native, was instantly recognizable and worked steadily for more than four decades.
He appeared in such films as 1979's "The Warriors," 1994's "The Flintstones" and 2003's "Intolerable Cruelty," not to mention a horror résumé that included Zombie's "1,000 Corpses," "Oblivion" and "Oblivion 2," "Disturbed" and a 1994 parody, "The Silence of the Hams."
He was even more visible on television, with regular roles in "The Jeffersons" (as George Jefferson's bodyguard, Hugo) and "On the Air" (as Shorty the Stagehand), as well as guest shots on "Police Squad," "Laverne & Shirley," "Moonlighting," "thirtysomething" and "CSI."
"The Jeffersons" helped him immensely, he said in an interview with Twin Peaks Archive
. ("On the Air" was created by "Peaks" producers David Lynch and Mark Frost.)
"One week I was in NYC. Next week I was acting in L.A. on the No. 1 show in America, 'The Jeffersons,' " he said. "My role became a recurring character. The audience loved what I did. They laugh to this day."
He told Examiner.com
that though he'd been pigeonholed as a horror actor in his later years, he enjoyed whatever came along.
"I did a lot of comedy for many years. I did two films with Tim Conway and Don Knotts ('The Prizefighter' and 'The Private Eyes'). I worked for Woody Allen ('Stardust Memories'), 'Zapped,' 'Laverne and Shirley,' horror, comedy or drama."
As manager Brock said, "Character actors are sometimes the unsung heroes. So many people used him. He was a lifer with us, and we were a lifer with him."
True to the creed of the working actor, Keyes noted that "it's one job at a time."
Indeed, he said, the key was staying busy.
"I had a great time making 'House of 1000 Corpses,' " he replied to a question about favorite roles.
"Then again," he added, "it's great to work on anything."