The efficacy of fleroxacin versus that of vancomycin was assessed by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Animals were treated with fleroxacin (30 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg every 6 h) for 4 days. These antimicrobial agents were equally effective in clearing bacteremia, reducing bacterial counts in vegetations and tissues, and curing endocarditis. However, resistance to fleroxacin at fivefold the MIC arose in the test strain of S. aureus in 8% of animals that received the drug. We conclude that fleroxacin is as efficacious as vancomycin in this model of a serious systemic S. aureus infection, but modest resistance to fleroxacin may develop during therapy.