Riluzole has been reported to protect against the deleterious effect of cerebral ischemia by blocking glutamatergic neurotransmission. Here, we investigated whether acoustic trauma-induced cochlear excitotoxicity could be attenuated by riluzole. Cumulative intracochlear perfusion of riluzole completely abolished single-nerve fiber activity in the guinea pig cochlea and the compound action potential of the auditory nerve. Guinea pigs treated with riluzole (100 microM) showed significantly less hearing threshold shift than untreated guinea pigs, and presented no sign of dendritic damage in the cochlea observable by electron microscopy. When coapplied with glutamate, riluzole did not prevent glutamate-induced swelling of auditory nerve dendrites, suggesting that the protective effect of riluzole was mediated principally by inhibition of glutamate release from sensory inner hair cells.