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To compare the efficacy of topical linezolid (LZD) 1 mg/mL or 2 mg/mL to vancomycin (VA) 50 mg/mL for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) keratitis in rabbits.One hundred colony-forming unit (CFU) MRSA bacteria were injected intrastromally into rabbit corneas. Sixteen hours after the injection, 24 rabbits were randomly divided into 4 groups. Rabbit eyes were treated with 1 drop of topical LZD 1 mg/mL, LZD 2 mg/mL, VA 50 mg/mL, or isotonic saline every 15 minutes for 5 doses and then every 30 minutes for 14 doses. Eyes were examined before and after the treatment using slit-lamp biomicroscopy by 2 observers blinded to the study for the determination of clinical severity. Then, corneas were harvested for the quantification of bacteria and histopathology.There were no differences in clinical severity among the groups before and after the treatment in each eye. The mean CFU × 106 of MRSA recovered from the LZD 1 mg/mL, LZD 2 mg/mL, and VA 50 mg/mL groups were significantly lower than that recovered from corneas treated with isotonic saline. There was no statistically significant difference among the treatment groups in terms of CFU × 106. Epithelial erosion in the VA 50 mg/mL group was significantly worse than that in the other groups. LZD 2 mg/mL group had the lowest mean epithelial erosion values.Topical LZD showed activity against MRSA that was comparable to fortified VA in this experimental keratitis model.