Williams, a three-time champion here and this year's No.1 seed, lost the first five games of the match and though she did end up closing in somewhat, she never really found her range - she also had her thigh taped mid-match. Cepelova, ranked No.78 in the world, ended up pulling it out, 64 64.
"Obviously things didn't go great out there, but she was a great counterpuncher today and hit a lot of balls back," Williams said. "I really knew nothing about her game going into the match, so she played a really good match against me today. And it just wasn't my day - it just wasn't meant to be today."
It has only been three days since Williams won the Premier Mandatory-level Sony Open Tennis in Miami on a much different surface - hardcourts. Did the American feel it was too quick a turnaround?
"No," she said. "I actually made the turnaround really, really well. I'm really just dead. I need some weeks off where I don't think about tennis and can kind of regroup. I've had a long couple of years."
What about the thigh? "It doesn't really impact me so much. All credit to her. She did well today. She just tried really hard out there, and she played the best she can probably play. And I've made this transition many, many times before, so there's really no excuse. It just wasn't my day today.
"I'm going to go on a vacation, for sure. I need some time off. I just need to take a deep breath and regroup, and I think it will actually help me for the rest of the clay court season coming up."
Williams against Cepelova was one of five second round matches on Tuesday's schedule, and it wasn't the only upset, after Teliana Pereira outlasted No.8 seed Sorana Cirstea in a marathon, 36 63 76(0), coming back from a set and a break down and eventually winning the final point with a big ace.
The other three seeds in action advanced, with No.6 seed Eugenie Bouchard crushing Russian qualifier Alla Kudryavtseva, 62 60, No.7 seed Sam Stosur battling past Yaroslava Shvedova, 63 57 61, and No.9 seed Lucie Safarova rallying from 3-1 down in the third to beat Virginie Razzano, 26 64 64.
Bouchard needed just 58 minutes to win her match and won the last seven games in a row.
"There's still a few things I could do better," Bouchard said. "I think my serve wasn't as good as I wanted it to be in the first set, though it kind of got better as I went on. Just little things like that, and trying to keep taking the ball early, trying to move forward. I can always do things better."