Giles Simon, seeded No. 6, was upset by Colombian Alejandro Falla 6-1, 6-0.
Fifth-seeded Jerzy Janowicz hit 14 aces to dispense with Pablo Carreno 7-5, 7-6 (7), and Joao Sousa defeated Guillermo Garcia-Lopez 6-3, 7-5.
Two favorites of the home crowd, Fernandez Verdasco and Feliciano Lopez, both lost in straight sets. Qualifier Michal Przysiezny ousted Verdasco 6-3, 7-6 (1) after Julien Benneteau thrashed Lopez 6-3, 6-1.
World No. 3 and reigning champion David Ferrer debuts on Wednesday against Gael Monfils, while John Isner plays Ernests Gulbis and second-seeded Tommy Has faces Philipp Kohlschreiber in an all-German match.