Del Potro is one of only two men to have beaten Federer in a Grand Slam final
Defending champion Juan Martin del Potro has been forced to pull out of the US Open because of a persistent wrist injury.
The Argentine, 21, has not played since the Australian Open in January after suffering the injury and had surgery on it in May to try and cure the problem.
"I'm so sorry for my fans, sponsors and the people who care about me," he said.
"But I have only started practising in the last two weeks and unfortunately I cannot compete at the top level yet."
The news is a second major setback in 24 hours for tournament organisers, following the announcement on Friday that women's world number one Serena Williams will also miss the tournament because of a foot injury.
Reigning women's champion Kim Clijsters also suffered an injury scare this week but insists she will be fit to defend her title at Flushing Meadow, starting at the end of the month.
"It is unfortunate that Juan Martin has not recovered from wrist surgery in time to defend his US Open title," said US Open tournament director Jim Curley.
"We wish him all the best and look forward to his return to New York next year."
Del Potro became the first man other than Rafael Nadal to beat Roger Federer in the final of a Grand Slam tournament at the US Open last September, but began struggling with tendinitis in his right wrist the following month.
He still finished the 2009 season at a career-high fifth in the world rankings after reaching the final of the ATP World Tour Finals in London, losing to Nikolay Davydenko.
The Argentine then suffered a recurrence of the injury in the new year and continued to struggle with the problem at the Australian Open, losing in the fourth round to Marin Cilic.
Highlights - Davydenko beats Del Potro in O2 final