We tested the antibacterial activity of ophthalmic 0.3% ciprofloxacin against that of 5.0% cefazolin and 1.36% tobramycin in two experimental models of keratitis, using a methicillin-sensitive strain of Staphylococcus aureus and an aminoglycoside-sensitive strain of Pseudomonas aeruginosa, respectively. Both corneas of New Zealand white rabbits were intrastromally injected with either S. aureus or P. aeruginosa. Twenty-four hours later, each eye was topically treated hourly for 24 hours. In the S. aureus model, the control group received Tears Naturale Free (Alcon Laboratories, Inc., Fort Worth, TX), the ciprofloxacin group received 0.3%, ciprofloxacin and the cefazolin group received 5.0% cefazolin. In the P. aeruginosa model, the control group received Tears Naturale Free, the ciprofloxacin group received 0.3% ciprofloxacin, and the tobramycin group received 1.36% tobramycin. One hour after the last eyedrops were administered, the rabbits were killed, and their corneas were processed for quantification of bacteria. For the S. aureus model, the mean (±SEM) colony forming units (CFU) of the control, 7.1 x 106 (±4.0 x 106); ciprofloxacin, 6.4 x 102 (±1.6 x 102); and cefazolin, 1.3 x 103 (±1.8 x 102) groups were different (F=17.5; p=0.001). The ciprofloxacin and cefazolin groups were not different from each other (p=0.034). The mean (±SEM) CFU for the control group in the P. aeruginosa model was 2.8 x 108 (±1.7 x 107). All corneas in the ciprofloxacin and tobramycin groups were sterile. Short-term treatment with ciprofloxacin was an effective treatment when compared with both fortified cefazolin and fortified tobramycin in eradicating S. aureus and P. aeruginosa, respectively, in these rabbit models of bacterial keratitis.