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Purpose: 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., Methods: 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., Results: There were no differences in clinical severity among the groups before and after the treatment in each eye. The mean CFU × 10(6) 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 × 10(6). 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., Conclusions: Topical LZD showed activity against MRSA that was comparable to fortified VA in this experimental keratitis model.