PURPOSE The aim of the present study was to evaluate the effectiveness of topically applied tigecycline for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in a rabbit model. METHODS Experimental bacterial keratitis was induced in rabbits by a corneal intrastromal injection of 100 colony-forming units (CFUs) of MRSA bacteria. Sixteen hours after the injection, 28 rabbits were randomly divided into 4 treatment groups of 7 rabbits each. In each group, the rabbits' eyes were treated topically with 19 doses of topical tigecycline (10 or 50 mg/mL), vancomycin (50 mg/mL), or isotonic saline. Slit lamp examinations were performed before and after the inoculation by two observers masked to the study for the determination of clinical severity. Corneas were harvested for bacterial quantitation and histopathologic examination. RESULTS No significant differences were observed in the clinical scores between pretreatment and posttreatment in the 4 groups (P>0.05). The mean difference between the pretreatment and posttreatment clinical scores from the 4 treatment groups was also not significant (P>0.05). All treatment groups had significantly lower CFUs compared with the control group. There were no significant differences in the bacterial load among the treatment groups. The minimum inhibitory concentration (MIC) for tigecycline was 0.12 μg/mL, whereas the MIC for vancomycin was 2.2 μg/mL. The tigecycline 10 mg/mL group had the lowest mean epithelial erosion values among the treatment groups. CONCLUSIONS Topical tigecycline significantly reduced the bacterial load in infected rabbit corneas and may be as effective as vancomycin for the topical treatment of MRSA keratitis.