Interest in Mycobacterium fortuitum has increased since it was recognized as an emergent pathogen. The objective of this study was to screen a large number of drug combinations in order to evaluate the activity of classical and new potentially useful antibiotics against M. fortuitum. Twenty M. fortuitum clinical isolates were studied with 51 combinations of two drugs and 47 combinations of three drugs belonging to different families: fluoroquinolones, linezolid, macrolides, rifamycins, aminoglycosides, and carbapenems. Activity was determined in Mueller Hinton broth by seeing whether the cultures were negative after 4 days of incubation with the combination of antibiotics. The most active drugs were moxifloxacin and gatifloxacin, which were active against 15 of the 20 strains studied, followed by amikacin (14 of the 20). The combinations of gatifloxacin with rifampicin or rifabutin, moxifloxacin with rifampicin or amikacin, and ciprofloxacin with amikacin were the most useful against M. fortuitum, as they showed activity in 18 of the 20 strains studied. Linezolid, imipenem, and ertapenem showed poor activity in this experimental model when they were used on their own. Larger studies, both in vitro and in vivo, should be done to confirm the true usefulness of the new fluoroquinolones, alone or in combination, in the treatment of M. fortuitum.