Top-seeded Serena, who opens against Vitalia Diatchenko of Russia, is in a quarter that includes nine Americans, notably Sloane Stephens, Madison Keys and Venus, who she could meet in the quarter-finals.
Men's top seed Novak Djokovic of Serbia, the 2011 champion, begins against Brazilian Joao Souza and appears to have a smooth path to the quarters where he could find 14-times major winner Rafa Nadal of Spain, seeded eighth after a subpar season.
Third seed Andy Murray of Scotland, who won in 2012, had French Open champion Stan Wawrinka of Switzerland, the fifth seed, drawn into his quarter for another potential last eight showdown worthy of a final.
But first Murray must get through a blockbuster opening clash with talented young Australian Nick Kyrgios, who has made headlines this month for vulgar comments he directed towards Wawrinka that landed him a suspended ban and $25,000 fine.
Second seed Roger Federer, the all-time slam singles king with 17 titles, opens against Argentina's Leonardo Mayer and is seeded to face Czech sixth seed Tomas Berdych in the quarters before a possible semi-final against the Murray-Wawrinka winner.
Defending men's champion Marin Cilic of Croatia, seeded ninth, could face fourth seed Kei Nishikori of Japan in the quarters for a rematch of their 2014 U.S. Open final.
While various scenarios are suggested in the men's draw, the women's tournament is focused on Serena and her bid to add a record seventh U.S. Open title to her 2015 triumphs at the Australian Open, French Open and Wimbledon.
The world number one will have to bring her focus early.
Serena's second-round opponent could be Croatian Mirjana Lucic-Baroni, who pulled off a shock win over Simona Halep in the second round of this year's French Open.
Also posing threats in her quarter are eighth-seeded Czech Karolina Pliskova and 12th seed Belinda Bencic of Switzerland, who beat Serena in the Toronto semi-finals less than two weeks ago.
In the lower quarter of the top half, Russian third seed Maria Sharapova and Serbian seventh seed Ana Ivanovic are seeded to compete in the quarters for the chance to meet Serena in the last four.
Second seed Halep begins her tournament against New Zealander Marina Erakovic with dangerous floater Victoria Azarenka of Belarus lurking in her quarter.
Caroline Wozniacki, the fourth seed from Denmark, is seeded to meet fifth seed Petra Kvitova of the Czech Republic in the other quarter.
(Editing by Frank Pingue)
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