Alexander Zverev, the 2020 US Open runner-up, will miss this year's tournament as he recovers from surgery on his right ankle.
Zverev tore ligaments in the ankle during his semifinal match against Rafael Nadal at the French Open in June.
The 25-year-old German was on the verge of his first Grand Slam title two years ago at Flushing Meadows before Dominic Thiem rallied to beat him in a fifth-set tiebreaker.
It was the first time a man overcame a 2-0 deficit in the final of the event since Pancho Gonzalez did it against Ted Schroeder in 1949.
Zverev won the Olympic gold medal in Tokyo last year and then returned to the US Open semifinals, losing to Novak Djokovic in five sets.
American Stefan Kozlov moved into the main draw for the tournament which begins next Monday.
The news potentially means Rafael Nadal will be given the number two seeding for Flushing Meadows, which would allow him to avoid number one seed Daniil Medvedev until the final.
Reilly Opelka, who won two titles earlier this year, also withdrew Monday because of injury. He reached the fourth round of the US Open last year.
Fellow American Jack Sock took his place in the main draw.
AP/ABC
