Endophthalmitis remains a dreaded complication of intraocular surgery and penetrating eye trauma. Subconjunctival, topical, and systemic antibiotics have been largely ineffective in the treatment of endophthalmitis, whereas intravitreal antibiotics have proved efficacious. Methicillin-resistant Staphylococcus epidermidis has become an important pathogen in many infections, including endophthalmitis. Toxicity, clearance, and efficacy of intravitreal vancomycin were evaluated in the treatment of experimental methicillin-resistant S. epidermidis endophthalmitis. No evidence of retinal toxicity was found and therapeutic levels were demonstrated six days after injection. The treated rabbit eyes showed a marked beneficial effect when compared to the untreated eyes. If experience confirms the safety of intravitreal vancomycin in human eyes, vancomycin should be considered the drug of choice for methicillin-resistant S. epidermidis endophthalmitis.