Twice former winner Serena Williams will test her fitness against Taiwan's Yung-Jan Chan when the U.S. Open starts at Flushing Meadows on Monday.
The eighth-seeded American, who has been battling knee and ankle problems in the build-up to the final grand slam of the season, opens up proceedings on the Arthur Ashe court.
She is followed by Spanish men's second seed Rafael Nadal, seen as one of the biggest threats to favourite Roger Federer who starts his title defence on Tuesday.
Nadal faces American Bobby Reynolds before Serena's older sister Venus, the Wimbledon champion and 10th seed, plays Japan's Rika Fujiwara.
Weather permitting - and the forecast is for thundery showers on Monday - Russian top seed Maria Sharapova will start her bid against Greece's Eleni Daniilidou in the night session.
American Andre Agassi, possibly playing in his final U.S. Open, plays Romania's Razvan Sabau in the final match on the Arthur Ashe court.
Two other leading women's contenders also play their first round matches. In-form Belgian fourth seed Kim Clijsters faces Germany's Martina Muller and Russian defending champion Svetlana Kuznetsova plays compatriot Ekaterina Bychkova.
Argentine trio Guillermo Coria, Gaston Gaudio and Mariano Puerta, seeded eighth, ninth and 10th respectively, are also in action.