The efficacy of ofloxacin was compared with that of vancomycin in the therapy of experimental Staphylococcus aureus endocarditis. Rabbits infected with either a methicillin-susceptible (MSSA-1199) or a methicillin-resistant (MRSA-494) test strain were treated with ofloxacin (20 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg of body weight every 6 h) for 4 days. The antimicrobial agents were found to be equally effective in clearing bacteremia and in reducing bacterial counts in vegetations and in renal and splenic tissue of animals infected with either test strain. The drugs were of equal efficacy in curing MRSA-494 endocarditis. No resistance to ofloxacin emerged in either test strain during therapy. We conclude that in this model ofloxacin is as efficacious as vancomycin and that, unlike for other fluoroquinolones we have evaluated, resistance to the drug does not develop during therapy of this serious S. aureus infection.