Rafael Nadal pulled out of his US Open title defence this month because of a wrist problem, the world number two said on Monday.
The 28-year-old Spaniard sustained the injury in practice last month and has been training with a cast on his right wrist, forcing him to miss the Rogers Cup in Toronto and last week's Cincinnati Open.
"I am very sorry to announce I won't be able to play at this year's US Open," Nadal said on his Twitter feed and on Facebook.
"I am sure you understand that it is a very tough moment for me since it is a tournament I love and where I have great memories from fans, the night matches, so many things.
"Not much more I can do right now other than accept the situation and, as always in my case, work hard in order to be able to compete at the highest level once I am back."
The 14-times Grand Slam winner also triumphed at Flushing Meadows in 2010.
Despite missing the entire North American hardcourt campaign, Nadal had hoped to compete in New York, previously posting a picture of himself working on court with his uncle and coach Toni with a black wrist support clearly visible.
The left-hander won his ninth French Open title in June but has not played since losing in the fourth round to Australian Nick Kyrgios at Wimbledon on July 2.
It is another worrying setback for Nadal who has had to battle back from injuries several times in his brilliant career.
After being sidelined for seven months with a knee injury, he returned last season to win 10 titles including Grand Slams in Paris and New York.
Injury also caused Nadal to miss out on a Wimbledon title defence in 2009 and the defence of his Olympic crown in 2012.
The winner of 64 career singles titles, he has claimed four trophies this year and has set no time frame for a return to competition.
The US Open starts on August 25.
Image: Rafael Nadal of Spain
Photograph: Scott Heavey/AELTC/Pool/Files/Reuters