Mycobacterium genavense is a recently described agent which can induce disseminated infections in patients with AIDS. Up to now, no standard approach to treatment has been defined and patients have been treated empirically with antibiotics used for treating infections caused by other nontuberculous mycobacteria. In this study, we compared the effectiveness of ciprofloxacin, amikacin, ethambutol, clarithromycin and rifabutin in the treatment of an animal model of M. genavense infection in C57BL/6 mice. Antimycobacterial treatment was started 4 weeks after an intravenous bacterial challenge and was continued for 30 days. Treated and control mice were killed at days 15 and 30 of treatment and the number of viable bacteria in their spleens was counted. Treatment with clarithromycin (50 mg/kg/day sc) and rifabutin (20 mg/kg/day po) was found to decrease the bacterial counts in the spleens significantly as early as 15 days after the onset of treatment (P < 0.01). The effect of treatment was more pronounced after 30 days of treatment (P < 0.001). Amikacin (25 mg/kg/day sc) and ethambutol (50 mg/kg/day sc) were found to decrease significantly the cfu in the spleens only after 30 days of treatment (P < 0.01). Ciprofloxacin (25 mg/kg/day sc) was ineffective in the experimental conditions used here.