Third seed Maria Sharapova was stunned on her return to action at the Western and Southern Open, losing to American starlet Sloane Stephens.
Four-time grand slam champion Sharapova had not played since crashing out in the second round at Wimbledon in June due to a hip injury.
Former world No. 1 Sharapova looked on course to make a victorious comeback in Cincinnati when she took the first set 6-2 against her 17th-ranked opponent.
But Stephens bounced back, recovering from 2-6 0-2 down to take the match 2-6 7-6 (7-5) 6-3 and register her second career victory over a top-three ranked player.
"It definitely started out a little rough for me, but I'm glad I was able to turn it around and start playing some good tennis in the second and third sets," 20-year-old Stephens told the WTA's official website.
"At the start of the second set I was just going to start going for my shots a little more and hoped they would just go in. I'm glad I started hitting and finding a rhythm. That kind of helped me out for the rest of the match.
"Obviously when you're playing someone who's No.3 in the world, you know they're No.3 for a reason and they're going to be tough. You've got to go out and play your hardest. But when you think about it, you're like, 'Okay, I'm playing Sharapova.' Like, you've got to get your mind right."
Sharapova was quick to credit Stephens but she was disappointed she was unable to continue the form she showed in the match's opening set.
"I didn't continue what I was doing well for the first set and a half, and that hurt me," explained the 26-year-old. "I stopped being patient. I started making a lot more errors, especially off the first ball. Just errors I shouldn't make.
"Obviously I haven't played in a long time, but I've got to be ready from the first match. So it's disappointing, but that's how it goes in this game."
Second seed Victoria Azarenka had no such problems, beating American Vania King 6-1 7-6 (8-6).
Belarus' Azarenka missed last week's event in Toronto with a back injury, but showed she was in good shape by recovering from 0-3 in the second set to take the match in one hour and 41 minutes.
Azarenka and Sharpova both entered the tournament at the second round stage.
"I think the beginning of the second set wasn't very good for me," Azarenka said after advancing into the third round.
"There were quite a few unforced errors and just really fast mistakes that didn't happen in the first set. It went kind of quickly, but I was glad that I could turn it around there and come back even stronger.
"Then there was competitiveness. She was already in the game and playing at a much higher level than before, and going for her shots. So I had to stay with her and just take my opportunities, and I did.
"There was a little bit of inconsistency today, but first matches can be tricky. I just want to think about what I need to improve for my next match. That's the most important thing for me going forward."
Wimbledon finalist Sabine Lisicki crashed out after losing her first-round match against former world No. 1 Jelena Jankovic.
Meanwhile 17-time grand slam champion Roger Federer began his defense of the men's title with a battling 6-3 7-6 (9-7) win over Germany's Philipp Kohlschreiber.
The fifth seed, playing for the first time since losing to Kohlschreiber's compatriot Daniel Brands at a clay-court event in Gstaad, Switzerland, is bidding for a record sixth win at the Ohio event.
"I think it was a match where I had to sort of just fight to come through," the 32-year-old told the ATP Tour's official website. "I was playing really well at times, and then sometimes it was maybe a bit up and down.
"But assessing the performance overall, I'm very happy. It's good to be back and playing pain free. My mind's good. I was in a good place while I was playing, so it felt nice to win at the end."
Third seed David Ferrer is also into the third round thanks to a hard-fought 7-6 (7-5) 3-6 6-4 win over U.S. wildcard Ryan Harrison.