To determine the efficacy of a fluoroquinolone antibiotic in the treatment of methicillin-resistantStaphylococcus aureus(MRSA) keratitis, topical administration of 0.3% ciprofloxacin was compared with topical 5.0% vancomycin or 5.0% cefazolin in experimental infections in the rabbit eye. The infections were established by intrastromal injection of 100 colony forming units (CPU) of MRSA, which resulted in greater than 106CFU per cornea by 12 hr postinfection. Chemotherapy (one drop every 15 min) was given from 4–9, 10–15, or 10–20 hr postinfection. Early therapy (4–9 hr postinfection) with ciprofloxacin rendered all eyes free of bacteria; ciprofloxacin was significantly more effective than vancomycin or cefazolin. When treatment was initiated 6 hr later (10–15 hr postinfection), no corneas became free of bacteria, but ciprofloxacin was again more effective than vancomycin or cefazolin. Bacterial killing by ciprofloxacin after treatment from 10–20 hr postinfection was also significantly greater than that of vancomycin. Overall, the results show that ciprofloxacin is effective in killing methicillin-resistantStaphylococcus aureus, and is most effective when applied during the very early stages of infection.