Serena and Venus Williams will not be able to reprise their sibling rivalry in the year's last Grand Slam final.
The No. 1-seeded Federer and No. 3 Nadal were drawn into opposite halves of the field for the U.S. Open, which begins Monday.
They have played in seven major finals as Nos. 1-2, including at each of the other three Grand Slam tournaments, with Nadal holding a 5-2 edge.
But because Nadal recently fell to third in the rankings, there was a possibility the two men who have dominated tennis in recent years would wind up on the same side of the bracket in New York.
Instead, 15-time Grand Slam champion Federer has No. 4 Novak Djokovic and No. 5 Andy Roddick in his half. Federer, who is seeking a sixth consecutive U.S. Open championship, edged Roddick 16-14 in the fifth set of the Wimbledon final in July.
The Williams sisters won't have a rematch of their Wimbledon final, in which Serena beat Venus for her 11th Grand Slam singles title. That was the sisters' eighth all-in-the-family final at a major, and Serena leads 6-2. But at the U.S. Open, the second-seeded Serena and No. 3 Venus were drawn for a possible semifinal.
The draw took place Wednesday and was announced Thursday.
The potential men's quarterfinals are Federer vs. No. 8 Nikolay Davydenko, and Roddick vs. Djokovic in the top half; No. 2 Andy Murray vs. No. 6 Juan Martin del Potro, and Nadal vs. No. 7 Jo-Wilfried Tsonga in the bottom half.
Nadal could face Murray in the semifinals for the second straight year at the U.S. Open; Murray upset Nadal in 2008 to reach his first Grand Slam final.
Nadal's first Grand Slam action since his fourth-round loss at the French Open will start with an intriguing opponent: Richard Gasquet, the former top-10 player coming off a 2½-month suspension for testing positive for cocaine.
Federer starts off against American wild-card recipient Devin Britton, an 18-year-old who won the NCAA singles championship for Mississippi in May.
Federer, trying to become the first man since the 1920s to win the tournament six years in a row, could play two-time major champion Lleyton Hewitt in the third round, U.S. Davis Cup player James Blake in the fourth, and French Open runner-up Robin Soderling or U.S. Open Series winner Sam Querrey in the quarterfinals.
The women's quarterfinals could be No. 1 Dinara Safina vs. No. 5 Jelena Jankovic, and No. 4 Elena Dementieva vs. No. 6 Svetlana Kuznetsova in the top half; Serena Williams vs. No. 7 Vera Zvonareva, and Venus Williams vs. No. 8 Victoria Azarenka in the bottom half.
Venus Williams could wind up facing 2005 U.S. Open champion Kim Clijsters in the fourth round. Clijsters recently came out of retirement and is returning to the tournament for the first time since winning it.