On a star-studded day that was scheduled to include Serena Williams and Roger Federer in the evening session, top-seeded and defending champion Novak Djokovic cruised into the third round with a 7-5, 6-1 win over wild card Sam Querrey.
Federer, the third seed who was playing for the first time since Wimbledon, needed 61 minutes — not including a 61-minute rain delay — to defeat Juan Ignacio Londerom 6-3, 6-4.
Djokovic felt a little rusty in his first match since his epic Wimbledon final triumph over Federer on July 14.
"It was kind of a nervous start," he said. "I hadn't played in weeks. It took time to adjust. It was a tricky match against a qualify opponent. He's a big hitter. I was happy to be tested."
Two-time Grand Slam-champion Petra Kvitova didn't weather the rain delay as well as Federer. The sixth seed lost to Maria Sakkari 6-4, 2-6, 6-3.
Counting Serena Williams, Kvitova was one of six seeded women to withdraw or be eliminated on Tuesday in this U.S. Open tuneup. Thirteenth-seeded Angelique Kerber was knocked out by unseeded Anett Kontaveit 7-6 (7), 6-2, and 15th-seeded Qiang Wang lost to Su-Wei Hsieh 6-3, 6-4.
Two-time Australian Open champion Victoria Azarenka, who won Cincinnati in 2013, reached the second round after 12th-seeded Belinda Bencic retired because of an injured left foot while trailing 6-4, 1-0.
On the other hand, going small paid off big for Venus Williams but Tuesday didn't go as well for sister Serena.
On a day when back problems forced the younger Williams to withdraw before her second-round match, Venus Williams reached the third round of the Western & Southern Open with a 6-3, 3-6, 7-6 (4) upset of defending champion Kiki Bertens. Her key? Not going for it.
"I just tried not to go too big, because I can go so big and I have a lot of power and it's not always easy to control it," the 39-year-old Williams said. "So I'm trying to play smart instead of going hog wild, which is extremely easy to do."
Hours before her match was scheduled to begin, Serena Williams withdrew, citing the same back injury that forced her to retire from the Rogers Cup final on Sunday in Toronto. The injury raises questions about Serena's fitness ahead of the U.S. Open, which starts August 26.
"I came to Mason on Sunday and have tried everything to be ready to play tonight, and was still hopeful after my practice this morning, but unfortunately, my back is still not right, and I know I should not take to the court," Serena, winner of 23 Grand Slam titles and a two-time champion at Cincinnati, said in a statement.
Venus, a seven-time Grand Slam champion, is the oldest woman in the draw. She has made her deepest Cincinnati run since reaching the 2012 semifinals.
"It was just a second round, though," Venus said. "For me, it's just round-by-round. I have a third round to play. I'm ready for the next round."
Bertens, seeded fifth, rallied from deficits of 3-0 and 5-2 in the third set to force a tiebreaker. The 2-hour, 17-minute match ended when she sailed a forehand wide.
Meanwhile, Madison Keys, the 16th seed, pulled out a 6-7 (4), 7-6 (5), 6-4 win over two-time Grand Slam winner and 2017 Cincinnati champion Garbine Muguruza.
On the men's side, Stan Wawrinka advanced with a 5-7, 6-4, 7-6 (4) victory over Grigor Dimitrov, and fourth-seeded Dominic Thiem withdrew because of illness.
In a match that lasted 2 hours, 34 minutes, Dimitrov fought off two match points in the eighth game of the third set and forced a tiebreaker. Wawrinka closed out the match with an ace.
Wawrinka next faces qualifier Andrey Rublev, who advanced with a 6-7 (4), 6-4, 6-2 victory over 15th-seeded Nikoloz Basilashvili.
Daniil Medvedev, the ninth seed and runner-up to Rafael Nadal at last week's Rogers Cup in Montreal, beat Kyle Edmund 6-2, 7-5.