Federer, whose five-set loss in the final to Juan Martin del Potro last year ended a 35-match winning streak dating to 2005, goes up against another Argentinian in the shape of little-known Brian Dabul in the late match on the Arthur Ashe Stadium Court.
Clijsters, whose triumph last year just weeks after she stepped out of retirement was one of the sports stories of the year, takes on Greta Arn of Hungary in the second match in the dayside session on the same court.
Also due to be in action were French Open finalist Robin Soderling of Sweden, who plays Austrian qualifier Andreas Haider-Maurer, and 2003 champion Andy Roddick of the United States, who faces Stephane Robert of France.
Venus Williams, who carries home hopes of a win following the withdrawal through injury of sister Serena, starts against Roberta Vinci of Italy.
