OBJECTIVE Transtympanic administration of the antioxidant N-acetylcysteine or lactated Ringer's solution onto the round window membrane will prevent cisplatin ototoxicity in the guinea pig model. BACKGROUND Cochlear ototoxicity is a well-known side effect of cisplatin administration, with the mechanism of injury thought to rest in oxidative damage to the outer hair cells. However, previous attempts at transtympanic antioxidant delivery have met with varied success. We present an effective method of counteracting cisplatin ototoxicity via the transtympanic application of lactated Ringer's solution or N-acetylcysteine. METHODS Baseline distortion product otoacoustic emission measurements were obtained. Intraperitoneal cisplatin was administered to a cumulative dose of 20 mg/kg. The middle ears were either untreated (control) or filled with normal saline (negative control), 2%N-acetylcysteine diluted in normal saline (treatment), or lactated Ringer's solution (treatment) via anterosuperior quadrant myringotomies. Posttreatment distortion product otoacoustic emissions were obtained. RESULTS Animals in the untreated control group and the negative control normal saline group demonstrated consistent obliteration of distortion product otoacoustic emissions. However, those receiving either lactated Ringer's solution or 2%N-acetylcysteine diluted in normal saline demonstrated significant preservation of distortion product otoacoustic emissions. The treatment regimen was well tolerated, with minimal animal loss. CONCLUSIONS We have demonstrated the efficacy of transtympanic lactated Ringer's solution and N-acetylcysteine in the prevention of cisplatin ototoxicity using a guinea pig model. The possible mechanisms for the high efficacy of lactated Ringer's solution are discussed in detail.