A prospective two-month epidemiologic and histologic study of all melanocytic nevi biopsied (n = 434) at the University of Oklahoma Health Center was undertaken. Melanocytic nevi with papillomatous features (PAP) (n = 50) were found to occur predominantly in females (females = 44, males = 6; p < 0.01 adjusted for sex distribution of all melanocytic nevi). Immunohistochemical analysis of melanocytic nevi revealed concordance between PAP and intracytoplasmic nevocellular staining for estrogen-inducible pS2 protein. Melanocytic nevi without papillomatous features failed to stain for pS2 protein. These results suggest a hormone responsiveness exclusive of patient sex which may influence the pathogenesis of these distinctive melanocytic nevi.