One hundred matches and counting for Federer at the US Open — but is there cause for concern for the Swiss?

Playing his 100th match at the US Open in 19 years is yet another marker of just how good Roger Federer has been — and for so long.

But his 3-6, 6-2, 6-3, 6-4 second-round win over 99th-ranked Damir Dzumhur suggests it could be a struggle for the 20-time grand slam winner to get to an appetizing rematch with men’s favorite Novak Djokovic in the semifinals.

Usually racing out of the blocks and suffocating opponents, Federer has lost the first set in his opening two rounds at a major for the first time ever in his career.

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On Monday in New York, it was Indian qualifier Sumit Nagal who grabbed the first set.

Is the 38-year-old still reeling from a gut-wrenching defeat to Djokovic in the Wimbledon final last month or was he simply feeling the effects Wednesday of competing under the roof on Arthur Ashe Stadium, where it is seemingly more difficult to breathe?

Last year outdoors on Ashe, Federer conceded the conditions got to him in a fourth-round reverse to John Millman. That evening, though, was much hotter.

Or is it nothing of concern, really, a rare yet minor blip?

His coming matches are sure to tell us more and the weather might have benefited Federer in one respect.

Advantage for Federer?

He will next face either pal Lucas Pouille or Britain’s Dan Evans, and the persistent rain means their second-round match might only start Thursday, leaving the winner with no rest for the Federer tussle.

Like their two previous contests — back to back in 2015 at the French Open and Wimbledon — Federer and Dzumhur put on a show thanks to dazzling variety and shotmaking.

The 5-foot-9-inch Bosnian — ranked as high as 23rd last year — raced to a 4-0 lead as Federer’s forehand went awry. Not only did he take the first set, but Dzumhur held a break point to start the second.

No wonder one of Federer’s twin daughters looked slightly nervous in the stands.

Federer, though, saved it and would save six of eight break points altogether.

At times the usually unflappable Federer let his frustration show, like when he missed a backhand overhead in the third set, a set where Dzumhur was visited by the trainer for an apparent abdominal issue.

But Federer ultimately collected his 87th victory at the US Open on Wednesday. If he reaches 92 next week, he would end the longest title drought for him at any major having last triumphed in the Big Apple in 2008.

Another legendary grand slam champion will have to wait until 2020, meanwhile, to end her own grand slam drought stretching to 2008.

Venus exits after coffee break

Venus Williams, a year older than Federer at 39, fell to No. 5 seed Elina Svitolina 6-4, 6-4 under the roof on Louis Armstrong Stadium despite an acrobatic volley to fend off one match point in a game lasting more than 15 minutes deep in the second. Svitolina — a Wimbledon semifinalist this summer — needed six match points overall to prevail.

Don’t ask Williams — who wanted a coffee on court for the second straight tournament — about retirement, though. She has already said she intends on playing in 2020, which is also an Olympic year.

Djokovic meets Argentina’s Juan Ignacio Londero while Williams’ younger sister, Serena, plays 17-year-old Caty McNally in Wednesday’s night session on Ashe. Serena Williams thumped Maria Sharapova in Monday night’s marquee encounter.