Five-time champion Roger Federer could find himself up against Novak Djokovic in the quarter-finals of the US Open, where Serena and Venus Williams could meet in a third-round blockbuster.
Federer, the second seed, opens against Japan's Yoshihito Nishioka, anchoring a bottom quarter of the men's singles draw announced Thursday that also features sixth-seeded Djokovic, the reigning Wimbledon champion who bested the Swiss great in the final at the Cincinnati Masters last week.
Fourth-seeded Alexander Zverev and seventh-seeded Marin Cilic, the 2014 US Open champion, are also in Federer's half of the draw. So is mercurial Australian Nick Kyrgios, the 30th seed who could face Federer in the third round.
"Of course Novak and Roger, they are doing very well and especially they like the hard courts," top seed and defending champion Rafael Nadal said as the draw was revealed in Lower Manhattan. "Let's see. Let's see what's going on."
Spain's Nadal opens his defense against a familiar foe in fellow Spaniard David Ferrer in a rematch of their 2013 French Open final.
It will be a 31st career meeting between the Davis Cup teammates, with Nadal leading the series 24-6. If he advances on schedule to the quarters, Nadal could encounter fifth-seeded Wimbledon finalist Kevin Anderson in a rematch of last year's Flushing Meadows final.
Andy Murray, playing his first Grand Slam since Wimbledon of last year and still battling to regain full fitness in the wake of January hip surgery, was handed a relatively gentle return to the major stage, drawing Australian James Duckworth, ranked 445th in the world, in the opening round.
If the Scot, who won his first Grand Slam title at Flushing Meadows in 2012, gets past Duckworth he would face either Fernando Verdasco or Feliciano Lopez in the second round before a possible third-round clash with third-seed Juan Martin del Potro.
Argentina's del Potro, the 2009 US Open winner, opens against a qualifier.
In the same quarter, eighth-seeded Grigor Dimitrov of Bulgaria received a nightmare draw: a first-round meeting with 2016 champion Stan Wawrinka, who received a wild card after missing last year through injury.
Wawrinka, a three-time Grand Slam champion, ousted Dimitrov in the first round at Wimbledon in July.
On the women's side, the Williams sisters feature in a talent-laden top quarter headed by world number one Simona Halep.
Serena, seeking a record-equalling 24th Grand Slam title, is seeded 17th despite her world number 26 ranking, US Open officials taking into account her six titles at Flushing Meadows in determining her seeding for the tournament she missed last year as she gave birth to her daughter Olympia last September 1.
Serena opens against Poland's Magda Linette, but her seeding won't protect her from a possible third-round clash with her 16th-seeded sister.
It would be their earliest meeting in a Grand Slam since Venus beat Serena in the second round of the 1998 Australian Open.
But Venus faces a potentially difficult first round match against 2004 champion Svetlana Kuznetsova, who received a wild card into the main draw as she continues her return from left wrist surgery.
- Halep seeks second major -
Halep, gunning for a second major of the year after her victory at Roland Garros, opens her campaign against Estonian Kaia Kanepi, a quarter-finalist last year.
The Romanian has impressed in the hardcourt build up to the US Open, her runner-up finish in Cincinnati last week following a victory in Montreal -- where she beat defending US Open champion Sloane Stephens in the final.
Stephens, the third seed, faces Russian Evgeniya Rodina in the first round, with the winner to face a qualifier in the second round. Should Stephens get through she could find former world number one Victoria Azarenka waiting in the third round.
Wimbledon champion Angelique Kerber, seeded fourth, faces Russian Margarita Gasparyan in the first round, while in the same quarter Maria Sharapova opens against a qualifier and sixth-seeded Caroline Garcia of France faces Briton Johanna Konta.
Second-seeded Caroline Wozniacki, who has battled injury since winning her first Grand Slam title at the Australian Open, faces a tough first-round clash with former US Open winner Samantha Stosur of Australia.