Japanese fourth seed Kei Nishikori, last year’s runner-up, crashed out Monday in the first round of the US Open while Serena Williams’ path to tennis history lost several major obstacles.

The year’s final Grand Slam tournament began with drama on the Flushing Meadows hardcourts as 41st-ranked Frenchman Benoit Paire saved two match points and rallied to defeat Nishikori 6-4, 3-6, 4-6, 7-6 (8/6), 6-4.

Top-10 women’s seeds Ana Ivanovic, Karolina Pliskova and Carla Suarez Navarro exited with opening-match losses, leaving 12th seed Belinda Bencic as the top-rated foe in Williams’ half of the draw.

Three-time defending champion Williams, who lost to Bencic in a Toronto semi-final, could face the Swiss teen again in the quarter-finals.

Williams is chasing the first calendar Grand Slam since Steffi Graf in 1988 and a 22nd career major title to match Graf’s Open Era record.

Paire, who had never before beaten a top-five foe, fired 21 aces to only three for Nishikori and blasted 64 winners, 30 more than Nishikori, with 67 unforced errors, 31 more than the Asian number one.

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Nishikori led the tie-breaker 6-4 but swatted a forehand long, watched Paire smack two service winners and then netted a forehand to force a fifth set.

Paire, who won his first ATP title last month at Bastad, broke for a 3-2 lead and held to the finish after three hours and 14 minutes.

Marin Cilic won his opener 6-3, 7-6 (7/3), 7-6 (7/3) over Argentine qualifier Guido Pella.

On the women’s side, Slovakia’s 50th-ranked Dominika Cibulkova ousted seventh-seeded Ivanovic 6-3, 3-6, 6-3, delivering the Serb star’s first US Open first-match exit since 2009.

After the injury-forced withdrawal of Russian third seed Maria Sharapova, Ivanovic had been Williams’ top-ranked rival.

That status fell to Czech eighth seed Pliskova, who lost to American Anna Tatishvili 6-2, 6-1, and to 10th seed Suarez Navarro, who lost to Czech Denisa Allertova 6-1, 7-6 (7/5).

One Williams rival who advanced was her older sister Venus, a seven-time Grand Slam champion and US 23rd seed who outlasted Puerto Rico’s Monica Puig 6-4, 6-7 (7/9), 6-3.

Venus could play Bencic in round three. World number one Djokovic meets Brazil’s Joao Souza while Spanish eighth seed Nadal, a possible quarter-final foe for Djokovic, faces Croatia’s Borna Coric, who won their first meeting last year at Basel.