Defending champion Todd Hamilton failed to produce the brilliance of Troon last year as he missed the Open cut, which fell at one over par.
The American, who stunned Ernie Els to win a play-off last year, shot a 74 in the second round to end on four over.
The 2003 Open champion Ben Curtis also missed out along with Fred Funk, Jim Furyk, Davis Love and Stewart Cink.
Lee Westwood and Ryder Cup captain Ian Woosnam were also casualties, along with Angel Cabrera and Paul Casey.
"I didn't play well and I'm disappointed with that," said Hamilton.
"I'm not a big fan of the greens here. They are very, very much slower than what we are used to in the States.
"It's a course you need to play a lot to get accustomed to the conditions, a lot more than I have."
Jack Nicklaus, in what has turned out to be his his final Open appearance, also suffered an premature exit after a determined level-par 72 left him on three over.
Britain's 1969 champion Tony Jacklin was another legend to depart the championship, finishing 11 over after a 76, but Tom Watson made it.
Hamilton, having also carded a 74 in the opening round on Thursday, had birdies at the first, ninth and 17th.
But three bogeys and a double bogey at the 13th cost him dearly.
Westwood, who resumed on five over, looked like he was going to survive for the weekend after bagging five birdies in his second round.
But his hopes were dashed by a triple-bogey seven at the 17th and his 70 was not enough.
Woosnam shot a 73 in Thursday's first round and never got going in the second as a 75 saw him finish on four over.
Former Masters champion Mike Weir also missed the cut after adding a disappointing 75 to his 76 for a seven-over total.
American David Toms disqualified himself from the Open on Friday morning.
The Ryder Cup star believes he may have hit a moving ball while holing out for a double-bogey six on the 17th during his first round on Thursday.
"It was just one of those iffy areas about whether or not a rule was violated and I was the only one that saw it," said Toms, who carded a 74.
"I might have hit a moving ball when I went to tap-in and I just felt it was better that I disqualified myself."