Objective:To explore the protective effect of sound preconditioning against ototoxicity induced by cisplatin and its possible mechanism with respect to the nitric oxide (NO) pathway. Methods:Albino guinea pigs were divided into silent control, CDDP,sound preconditioning and sound preconditioning+CDDP groups. The animals of the CDDP group were injected with cisplatin intravenously 8 mg/kg b.w. The animals in the sound preconditioning were exposed to white noise at 85dB SPL, 5h/d, for 10 d (sound preconditioning). The animals in the sound preconditioning+CDDP group were treated with sound preconditioning first and then administrated with cisplatin intravenously 8 mg/kg b.w. Hearing thresholds of auditory brainstem responses (ABRs) of all animals were measured to evaluate hearing function. Hair cell loss was estimated via surface preparation. Cochlear tissue was assayed for measurement of NO level and immunohistochemistry method was used for inducible nitric oxide synthase (iNOS) analysis. Results:There was no significant difference between the silent control and sound preconditioning animals with respect to either functional or histological measures. Among the animals in the CDDP group, there was a significant elevation of threshold at the high test frequencies after administration compared with the silent control group (P＜0.05). Morphological examination showed that there was obvious loss of the OHC, especially in the third row of the basal turn. The NO level and immunoreactivity to iNOS in this group were higher and more intensive than those of the silent control group (P＜0.05). The ABR thresholds in the sound preconditioning + CDDP group were much lower than those of the CDDP group (P＜0.05). Slight sporadic loss of OHC was found in this group. The immunoreactivity to iNOS and the level of NO in cochlea decreased significantly compared with the CDDP group (P＜0. 05). Conclusion:It is suggested that sound preconditioning, to some extent, provides protective effect against ototoxicity of cisplatin. The excess synthesis of NO induced by the over-expressed of iNOS may be involved in the CDDP induced ototoxicity. The possible mechanism is related to suppression of the NO pathway.