Watson withdraws from Royal Troon
The 54-year-old American, who has a shoulder injury, will miss the championship for only the second time since his debut - and first victory - at Carnoustie in 1975.
He had a back problem in 1996.
Watson managed joint 18th at Sandwich last year, one of just a handful of players to break 70 on the final day.
His Troon win came in 1982, when Nick Price fell away to leave Watson a stroke clear of the Zimbabwean and Britain's Peter Oosterhuis.
It followed his triumphs at Carnoustie, Turnberry and Muirfield and when he also won at Birkdale the following year he was one short of Harry Vardon's record of six titles.
The chance to equal that came at St Andrews in 1984, but in one of the most exciting finishes ever, Seve Ballesteros birdied the 18th and Watson bogeyed the 17th to lose by two.
Watson's compatriot Fred Funk, who has admitted he hated the time he spent at the Open last year, has also pulled out.
The 48-year-old lies ninth in the race for places in the US Ryder Cup side, but has joined two other possible teammates, Scott Hoch and Kirk Triplett, in turning down the chance to play.
At Sandwich Funk had rounds of 75 and 80 to miss the halfway cut by five shots.
He said later: "I went to Royal St George's and got in some terrible habits. I shouldn't say I hated the golf course, but I hated the golf course."