The incidence of malignant melanoma of the skin has increased rapidly among white people during the last decade. Although the pathogenesis of malignant melanoma is not clear, epidemiologic data and experimental work indicates that ultraviolet (UV) radiation plays a critical role in tumorigenesis. Recent data implicate peroxidative reactions in UV-carcinogenesis and clearly demonstrate that selenium (Se) confers protection, in part by inducing cellular-free radical scavenging systems and by enhancing peroxide breakdown, thus enhancing the capacity of the cell to cope with oxidant stress. With this in mind, we investigated the Se status of 101 patients with malignant melanoma. Our study revealed significantly lower Se levels in the sera of melanoma patients than of controls. Although patients in all clinical stages had lower Se levels than the controls, patients in stage III (disseminated melanoma) had the lowest levels. Separate analysis of histogenetic subtypes of melanoma revealed that lentigo maligna melanoma (LMM) and superficial spreading melanoma (SSM) had the strongest association with depressed Se serum levels. Our results, showing for the first time that malignant melanoma is associated with low Se concentrations, are consistent with results of epidemiologic studies showing an inverse correlation between serum Se levels and certain cancers.