Top-seeded Novak Djokovic was upset by Tommy Robredo of Spain 7-6 (6), 7-5, in the round of 16 at the Western & Southern Open overnight.
Djokovic, who has never won the tournament, dropped the first set after fighting back from a 6-3 deficit in the tiebreaker.
Robredo failed to convert two match points before completing the upset with a slam on a short Djokovic lob.
Robredo had lost six straight matches against the Serb after winning their first encounter.
Earlier, Andy Murray fought off two late match points and edged John Isner of the US 7-6 (3), 6-4, 7-6 (2) to reach the quarterfinals.
Isner, who lost to Rafael Nadal in last year's final, had two chances to win the match with a 6-5 lead in the third set, but Murray salvaged both points before taking control with a mini-break for a 3-1 lead in the tiebreaker.
Stan Wawrinka shook off losing the first set to roll through the next two and advance with a 3-6, 6-0, 6-1 win over Marin Cilic of Croatia.
Wawrinka, the Australian Open champion, will meet unseeded Julien Benneteau of France in the quarterfinals.
Benneteau eliminated Jerzy Janowicz of Poland 7-5, 6-1.
Fabio Fognini of Italy also needed three sets to get past Yen-Hsun Lu of Taiwan 3-6, 6-3, 6-3.
In women's play, top-seeded Serena Williams continued her pursuit of her first title in this tournament with a 6-2, 6-2 win over Flavia Pennetta.
Williams immediately took command, breaking Pennetta's first serve of the match.
Williams, who's never won this tournament, also led, 5-0, in the second set.
''I got the early break, and I didn't let go,'' she said.
''That's what I wanted to do. She can try and come back. She tried to come back, I wanted to stay focused.''
Simona Halep of Romania also reached the quarterfinals with a 6-4, 7-5 win over Lucie Safarova of the Czech Republic, but Carla Suarez Navarro of Spain was upset by unseeded Elina Svitolina of Ukraine 4-6, 6-4, 6-4.