Rafael Nadal and Karolina Pliskova - the No. 1 seeds in the Western & Southern Open - advanced with straight-set wins Wednesday, while the rest of their brackets suffered more top losses.
Nadal sat out an hour-long rain delay and beat Richard Gasquet 6-3, 6-4 on Wednesday night, finishing it off with two of his eight aces.
Pliskova needed only 67 minutes to get a 6-2, 6-3 win over Natalia Vikhlyantseva, a solid showing as the defending champion. She'd never faced the Russian and wasn't sure what to expect.
"Obviously, I didn't know my opponent, so I don't think it was the best match," she said. "But as always, first rounds are not the best."
The rest of the hot, muggy day was highlighted by upsets.
Venus Williams' resurgent summer hit a bump when she was knocked out by a qualifier. Ashleigh Barty rallied for a 6-3, 2-6, 6-2 upset on a humid afternoon that played to her advantage.
Barty, ranked No. 48 on the ATP tour, had never beaten a Top 10 player - going 0-6 - before knocking off the ninth-ranked Williams.
Williams is enjoying a comeback season, reaching the finals at the Australian Open and Wimbledon at age 37. She faded in the heat and humidity on Wednesday against a player who is 3-13 career against Top 20 players.
"I'm going to take a break," Williams said. "Just have a rest and just go big. That's my plan."
After knocking off Williams, Barty had to head for her doubles match, still buoyed by the biggest win of her singles career.
"It really is a privilege to be able to share the court with Venus," Barty said. "She's an amazing champion and how she's still playing so well, still making Slam finals - it's amazing. To be able to share the court with her and play well today, it was really exciting."
No. 3 Angelique Kerber lost to Ekaterina Makarova 6-4, 1-6, 7-6 (11), with the Russian converting on her eighth match point to end a 2-hour, 39-minute match. Makarova also upset Kerber at Roland Garros this season.
Kerber fell behind 5-2 in the third set, rallied to a tiebreaker, then got up 8-7. She wasted her only chance to finish it off.
"The third set was a completely up-and-down set," Kerber said.
Makarova got cramps in both legs during the third set, and they got worse during the tiebreaker, forcing her to get treatment briefly.
"I had the match points, and then of course with the nerves, it kind of felt even more," she said. "It came back again during the tiebreak because it was great, long points and both of us running and running."
The men's bracket lost one of the hottest player of late.
Wild-card Frances Tiafoe broke through against No. 4 Alexander Zverev, who was coming off his second ATP Masters title in Montreal. The 19-year-old American hadn't taken a set in his two career matches against Zverev, but rallied for a 4-6, 6-3, 6-4 victory that ended Zverev's streak of 10 straight match wins.
Zverev won back-to-back titles in Washington and Montreal, leaving him little time to rest. It showed against Tiafoe, who was more aggressive as the match went along.
"I'm completely dead right now," Zverev said. "I have been dead for the past two days. I could have easily pulled the plug in the second set, but I'm not going to retire just because I'm tired. And he's too good of a player to beat when I'm in this stage."
The upsets further depleted both brackets, which were already thinned by injuries to top players. The men's bracket is without Roger Federer, Andy Murray, Novak Djokovic and defending champion Marin Cilic because of injuries. The women's bracket is missing Serena Williams, Victoria Azarenka and Maria Sharapova.