Purpose: To evaluate the effects of intravitreal moxifloxacin and moxifloxacin and dexamethasone combination in an experimental rabbit model of Staphylococcus aureus endophthalmitis. Methods: The right eyes of 24 rabbits weighing 2 to 3 kg were used. Ten thousand colony-forming units (CFU) of S. aureus in 0.1 ml saline solution were inoculated into the vitreous cavity. The eyes were randomly assigned to one of the four groups equally. Twenty-four hours after the inoculation of S. aureus, group 1 received 50 mu g moxifloxacin, group 2 received 50 mu g moxifloxacin plus 400 mu g dexamethasone, and group 3 received 1 mg vancomycin intravitreally. No treatment was given to group 4. Clinical examination scores were recorded. Vitreous aspirates were obtained for microbiological analysis Just before sacrifice, and the eyes were enucleated for histopathologic examination. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests. Results: In all treatment groups, mean number of CFU and histopathologic score were significantly lower compared with control group (p < 0.05), and the difference between treatment groups was not statistically significant (p > 0.05). The clinical score was not significantly different between groups (p > 0.05). Conclusions: Intravitreal injection of 50 mu g moxifloxacin was effective in the treatment of S. aureus endophthalmitis. Bacteriological, histopathologic, and clinical outcomes after treatment using moxifloxacin, moxifloxacin and dexamethasone combination, and vancomycin were comparable. Intravitreal moxifloxacin may be an option in the treatment of S. aureus endophthalmitis.