Second seed and defending champion Lleyton Hewitt was upset 6-3, 7-5 by Frenchman Julien Benneteau to cap a day of surprises at the Las Vegas Open on Wednesday.
Australian Hewitt, a three-times winner of the tournament, had reached the final in five of his six previous appearances in the event.
Fifth seed Potito Starace and number eight Nicolas Kiefer were also knocked out.
Benneteau, the world number 61, failed on his first attempt to serve out the match but broke Hewitt again and held to set up a clash with unseeded American Sam Querrey who needed less than an hour to eliminate Kiefer.
"It's a good win," Benneteau told reporters after reaching his second quarter-final of the year. "I'm very happy about this match and I hope to be fit like this in the quarter-final on Friday."
American qualifier Amer Delic set up a match against fourth seed Guillermo Canas of Argentina when Starace retired with a back injury after trailing 6-3, 3-0.
"It definitely feels good to get through for the first time," Delic, 25, said after reaching his first ATP quarter-final. "No better place to get lucky than in Vegas, I guess."
Querrey converted five of six break points to upset German Kiefer 6-3, 6-1.
"I played really well," the 20-year-old Californian said. "I started off a little sluggish but then just played solid and kept the ball to his forehand. I played aggressive, especially when I was returning his second serve."
Argentine Canas broke big-serving Australian Chris Guccione four times to win their second-round match 6-2, 7-5.
The 30-year-old from Buenos Aires held off a Guccione fightback in the second set to seal victory in just under an hour-and-a-half on the Stadium Court.
Serving for the match at 5-4, Canas saved three breakpoints before his towering left-handed opponent levelled at 5-5.
The Argentine, bidding for an eighth ATP title, then won the next two games to book a quarter-final clash with Delic.
"I feel great," Canas said. "Whenever you play a tough, big-serving player, it is always a danger but I feel very confident in my game. I am returning very well and I'm moving very well."
