Serena Williams' quest for a record 23rd Open era Grand Slam title starts against Russia's Ekaterina Makarova, while Novak Djokovic begins his U.S. Open title defense against Jerzy Janowicz.
Play begins Monday in the final major tennis tournament of 2016. First-round pairing were set Friday, two days after the top 32 seeds in men's and women's brackets were announced.
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Williams lost in the semifinals of last year's competition at the USTA Billie Jean King National Tennis Center in New York. That prevented her from achieving a calendar grand slam. She has won title this season, at Wimbledon, and lost in the finals at the Australian and French opens.
Things could get tricky for Williams with a potential third-round match against Ana Ivanovic, quarterfinal versus Simona Halep and a possible semi against sister Venus or Agnieszka Radwanska.
Angelique Kerber will be looking to displace Williams at the top of the rankings at the U.S. Open, and Polona Hercog will be her first opponent.
French Open champion Garbine Muguruza will face a qualifier in the first round. Olympic champion Monica Puig could be her third-round opponent.
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Men's draw
Djokovic seeks his 13th major title, but he lost at Wimbledon to Sam Querrey in the third round and to Juan Martin del Potro in the first round at the 2016 Rio Olympics.
Djokovic is joined in the top half of the draw by Rafael Nadal and Canada's Milos Raonic.
Andy Murray will face Lukas Rosol in his first match. He could face Kei Nishikori in the quarterfinals and Stan Wawrinka or Del Potro in the semis.