Seeded pair Tommy Haas and Fernando Verdasco were both eliminated in the second round of the US Men's Clay Court Championship in Houston.
Sixth seed Verdasco crashed out 6-3 6-2 to fellow Spaniard Ruben Ramirez Hidalgo while German Haas, seeded second, was beaten 6-3 6-3 by Lithuania's world number 77 Ricardas Berankis.
The other seeds in action all made it through, though Nicolas Almagro and John Isner were both pushed to deciding sets.
Top seed Almagro lost the first set to dangerous Frenchman Gael Monfils but came back to win 2-6 6-0 6-3 in a rapid 86 minutes, while Isner came through to beat fellow American Jack Sock 7-5 6-7 (3-7) 7-6 (7-3).
Argentina's Juan Monaco eased past another American, Tim Smyczek, 7-6 (7-5) 6-1 while seventh seed Paolo Lorenzi beat Italian compatriot Flavio Cipolla in similar fashion, 7-6 (7-4) 6-1.
There was further cause for the home crowd to celebrate as Robby Ginepri beat Martin Alund 6-2 4-6 6-4 and wild card Rhyne Williams beat Croatian lucky loser Ivo Karlovic 6-4 6-7 (5-7) 7-6 (7-3).
Jamie Murray will carry Britain's hopes in the doubles semi-finals after he and Australian John Peers beat the fourth seeds, Jonathan Erlich and Murray's former partner Eric Butorac, 6-4 6-2. Another Brit, Dominic Inglot, and his Filipino partner Treat Huey lost 6-4 7-5 to Johan Brunstrom and Jesse Levine.