World number one Roger Federer faces a stern test in the first round of the U.S. Open after being pitted against Spaniard Albert Costa in Wednesday's draw.
The Swiss number one seed, winner of the Australian Open and Wimbledon this year, has lost his last two meetings with the 2002 French champion, most recently at this year's Rome Masters.
Defending men's champion Andy Roddick meets 18-year-old wildcard Scoville Jenkins, who recently became the first African-American to win the USTA under-18 boys singles since it began in 1916.
Other highlights of the men's draw include eight-times Grand Slam winner Andre Agassi's clash with fellow-American Robby Ginepri and fourth seed Lleyton Hewitt's tricky opener against South African Wayne Ferreira.
Newly-crowned Olympic champion Nicolas Massu of Chile, the 10th seed, faces Jose Acasuso of Argentina.
In the women's singles, Belgian top seed Justine Henin-Hardenne will begin the defence of her crown against a qualifier, while second seed Amelie Mauresmo of France will play American Marissa Irvin.
Russian teenage sensation Maria Sharapova, aiming to follow up her stunning Wimbledon success, launches her assault on Flushing Meadows against American Laura Granville.
The leading home challengers all face Eastern European opponents.
Third seed Serena Williams, winner in 2002 and 1999, plays Sandra Kleinova of the Czech Republic, older sister Venus was drawn against Hungary's Petra Mandula while in-form Lindsay Davenport is up against Slovakia's Lubomira Kurhajcova.
French Open champion and fourth seed Anastasia Myskina begins her campaign against Slovakian Ludmila Cervanova.
The U.S. Open runs from August 30 to September 12.