CI-960 is a new fluoroquinolone with enhanced in vitro activity against gram-positive pathogens. The efficacy of the drug was compared with that of vancomycin by using the rabbit model of nafcillin- and ciprofloxacin-susceptible and -resistant Staphylococcus aureus endocarditis. Animals received intravenous therapy with CI-960, 20 mg/kg of body weight every 8 h, or vancomycin, 17.5 mg/kg every 6 h, for 4 days. In a comparison with the effects on untreated controls, both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues of animals infected with any of the test strains. In some cases, the efficacy of CI-960 was superior to that of vancomycin. The therapeutic activity of CI-960 was reduced, but still very good, against ciprofloxacin-resistant strains. One rabbit infected with such a strain and treated with CI-960 was found to harbor a small number of vegetation-associated organisms resistant to the drug at fivefold its original MIC; this was associated with a microbiological, but not a clinical, failure of therapy. We conclude that CI-960 is as effective as vancomycin is in this model of a serious systemic S. aureus infection, including that caused by strains resistant to ciprofloxacin. Increases in CI-960 MICs may develop during therapy of infections caused by strains highly resistant to ciprofloxacin, but they appear unlikely to occur in ciprofloxacin-susceptible strains.