Novak, who has four career titles, breezed to a 6-3, 6-3 victory over Armenian Sargis Sargsian. Novak, whose last title came here in 2001, will face Frenchman Paul-Henri Mathieu in the second round of this claycourt event.
Novak had to withdraw from this tournament last year due to an infection.
Mathieu won for the second time in 12 ATP matches this year with a 6-3, 6-1 triumph over German Philipp Kohlschreiber.
Juan Ignacio Chela routed Brazilian Andre Sa, 6-0, 6-2, while Gaston Gaudio dispatched Belgian Kristof Vliegen, 6-3, 6-4.
No. 6 Nikolay Davydenko of Russia became the first seed to fall. Frenchman Anthony Dupuis beat Davydenko, 7-6 (7-1), 7-6 (7-4).