Because of its prevalence and severity, Babesia microti infection is an important public health problem. The current treatment of choice is clindamycin plus quinine. However, in some cases other treatments are needed because of drug intolerance or relapse. The activity of azithromycin was investigated for treatment of babesiosis in the hamster model. All animals received vancomycin to prevent antibiotic-associated colitis. Quinine (250 mg/kg/day), azithromycin (150 mg/kg/day), and the combination of azithromycin and quinine were compared. A significant suppression of parasitemia was found in all treatment groups (combination had the greatest effect, followed by azithromycin, then quinine; P < .05). The mean survival was significantly prolonged in the combination group (P < .05). Azithromycin as monotherapy in a higher dose (300 mg/kg/day) also resulted in a significant prolongation of survival (P < .05). Spirogermanium and ciprofloxacin, which have been reported to have antimalarial activity, had no effect on parasitemia or survival in this experimental babesiosis model.