We have previously shown thryotropin-releasing hormone expression in nevi and melanoma. Thryotropin-releasing hormone regulation by leptin has been shown in the hypothalamus. The present study was therefore undertaken to evaluate leptin and leptin receptor in nevi and melanoma. Leptin receptor expression as assessed using an anti-leptin receptor antibody showed uniform expression throughout the lesion in 14 of 17 melanomas; 3 melanomas lacked leptin receptor immunoreactivity. In contrast, out of 15 nevi, 10 showed weak to moderate leptin receptor immunoreactivity, with positivity present only in the superficial dermal component. Thus, maturation was present in nevi but not in melanoma with the anti-leptin receptor antibody (P<0.0001). Anti-leptin antibody, in contrast, did not show a significant difference in maturation between nevi and melanoma. We also compared leptin receptor in Spitz nevi and melanoma, as the two can sometimes be difficult to distinguish. Spitz nevi showed moderate to strong immunopositivity. Of 19 Spitz nevi, 7 showed lack of maturation, a finding statistically significant from both melanoma and nevi. Our results suggest a role for leptin receptor in melanoma, and we show for the first time that melanomas show more intense immunoreactivity as compared to nevi (but not Spitz nevi) and that maturation with anti-leptin receptor antibody may be a diagnostically useful tool in distinguishing melanomas, especially nevoid ones, from nevi in difficult cases.