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Ofloxacin is a broad spectrum fluoroquinolone antibiotic with good ocular penetration. We investigated the potential for retinal toxicity associated with increased intraocular penetration following intensive topical, oral, and combined topical and oral administration. We confirmed ofloxacin concentrations in aqueous and vitreous following these forms of administration. Rabbits received either topical, oral, or a combination of oral and topical ofloxacin. Topical administration consisted of one drop of ofloxacin 0.3% drops given every thirty minutes for a total of eight doses. Oral ofloxacin was administered at a dose of 10 mg (4 mg/kg for average weight 2.5 kg rabbit) every 12 hours for a total of three doses. Six rabbits were followed longitudinally for 4 weeks for evidence of retinal toxicity by indirect ophthalmoscopy and serial ERGs. Electron and light microscopic histopathologic examination of the retina were performed 4 weeks following drug administration. To verify intraocular penetration, ten rabbits received identical dosing schedules followed by HPLC measurement of aqueous and vitreous drug concentrations at 1, 4, 8, 12, and 24 hours following dose completion. No evidence of retinal toxicity was detected by indirect ophthalmoscopy, electroretinography, or histopathological examination. Vitreous ofloxacin levels were highest after combined oral and topical administration, peaking at 0.892 microgram/ml 8 hours following dosage completion. The peak vitreous level following oral administration was 0.230 microgram/ml and 0.026 microgram/ml following topical administration. Peak aqueous humor levels were achieved one hour following drug administration and were 11.400 micrograms/ml after topical, 0.206 microgram/ml after oral, and 8.180 micrograms/ml after combined administration. Our study suggests that intensive topical and oral ofloxacin administration does not cause retinal toxicity in rabbits, despite achieving effective aqueous and vitreous humor antimicrobial concentrations.