The efficacy of three topical antibiotic treatments for Mycobacterium fortuitum (strain ATCC-6841) keratitis were compared in rabbits. Rabbits were treated with ciprofloxacin (3 mg/ml) or clarithromycin (20 mg/ml) or a combination of amikacin (100 mg/ml) and vancomycin (50 mg/ml). All three treatments significantly reduced the number of organisms in treated eyes compared to untreated, control eyes (all P values < .001). No significant difference in treatment efficacy was found between the three treatment groups (all P values > or = .48), although ciprofloxacin (3 mg/ml) was more effective than clarithromycin (20 mg/ml) after excluding outliers (P = .01). All treatments stabilized or reduced the size of stromal infiltrates after four days of therapy, whereas infiltrates continued to enlarge in untreated eyes. These results suggest that topical clarithromycin, topical ciprofloxacin, and combined amikacin and vancomycin may all be clinically useful for treating M. fortuitum keratitis. Both clarithromycin and ciprofloxacin were better tolerated than combined amikacin and vancomycin. This study supports the further development of clarithromycin, a new macrolide antibiotic, as a topical drug for treatment of M. fortuitum keratitis.