It is known that adrenocorticotrophic hormone (ACTH)-derived peptides, the so-called melanocortins, can reduce cisplatin-induced neurotoxicity. Recently, our group has found that cisplatin-induced ototoxicity can also be reduced or prevented by treatment with the synthetic melanocortin-like peptide, ORG 2766 (Hamers et al., 1994; De Groot et al., 1997). The present study was designed to investigate the possibly ameliorating effects of the physiologically more relevant naturally occurring neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) upon cisplatin ototoxicity and to compare its protective effects to those of ORG 2766. For eight consecutive days guinea pigs were treated with cisplatin at a concentration of either 1.5 mg/kg/day or 2 mg/kg/day. Animals were co-treated with either alpha-MSH (75 microg/kg/day), ORG 2766 (75 microg/kg/day), or a sham injection containing physiological saline. Electrocochleography and hair cell counts were performed. Treatment with 1.5 mg/kg/day cisplatin resulted in a large variability of the morphological and electrophysiological data, a variability that might have masked possible effects of ORG 2766 and alpha-MSH. Treatment with 2 mg/kg/day cisplatin caused less variable, severe reductions in the compound action potentials and cochlear microphonics combined with basal and middle-turn outer hair cell loss in five out of six animals. However, in the alpha-MSH co-treated groups, two out of six animals could be classified as normal, two animals as moderately affected and two animals as severely affected. In the ORG 2766 co-treated group we found three animals that were not affected and three animals that were severely affected. We conclude that the protective effects of alpha-MSH and ORG 2766 co-treatment are comparable and that alpha-MSH might be clinically useful in protecting against cisplatin-induced ototoxicity.