Lleyton Hewitt, the 12th seed, was sent crashing out as the Australian lost 7-6 (7/3) 6-4 to world number 59 Eduardo Schwank.
Fourth seed Fernando Gonzalez made a shock second-round exit at the Barcelona Open after losing to unheralded Spaniard Albert Ramos-Vinolas.
The world 166 had claimed his first ATP Tour win when he beat Michael Russell in the first round, but usurped that with a dramatic 6-4 6-7 (8/10) 6-3 success against Gonzalez.
Third seed Jo-Wilfried Tsonga enjoyed an easy afternoon on his Barcelona debut, beating Jan Hajek 6-3 6-2.
Tsonga, who turned 25 last Saturday, will next meet Spanish 15th seed Nicolas Almagro who he beat in the second round at Monte Carlo last week.
“Almagro is a great player and it will be difficult to get a win against him,” the Frenchman said.
“I beat him last week, but I was playing at home. This time it is him who is at home, and he’s going to get a lot of support, so I’m going to have to play a very solid match.”
Fifth seed Fernando Verdasco swept past another Frenchman, Richard Gasquet, 7-5 6-3 while former world number one Juan Carlos Ferrero improved his impressive clay-court record this year after Sergiy Stakhovsky retired from their match when trailing 6-3 4-2.
Ferrero, the 2001 champion, now has an 18-2 win-loss record on clay this season, which includes title victories at Costa do Sauipe and Buenos Aires.
Other seeds to progress where David Ferrer (eight), Jurgen Melzer (11), Thomasz Bellucci (13) and Feliciano Lopez (16).
Spanish duo Ferrer and Lopez were straight-sets winners against wildcard Marcel Granollers and Denis Istomin respectively.
Melzer struggled to end the run of Barcelona-born Oscar Hernandez, who fired 11 aces, 6-7 (4/7) 7-5 7-5 while Bellucci also took three sets to beat Victor Hanescu 6-2 1-6 7-5.
Elsewhere, Italian qualifier Simone Bolelli beat wildcard Alberto Martin and Guillermo Garcia-Lopez saw off lucky loser Teimuraz Gabashvili.
Ernests Gulbis and Thiemo de Bakker were straight-sets winners against Jeremy Chardy and Daniel Gimeno-Traver respectively.