The alpha(v)beta3 integrin has emerged as a key mediator in angiogenesis. Its role in tumor-induced angiogenesis is supported by its up-regulation in vivo in the vasculature of a number of different types of carcinoma. The potential clinical significance of alpha(v)beta3 expression on blood vessels in carcinomas is suggested by its association with tumor progression. Currently no information is available about the clinical significance of alpha(v)beta3 expression on the vasculature of lesions of melanocytic origin. Since we have previously found that alpha(v)beta3 expression on melanoma cells in primary lesions is associated with a poor prognosis, in the present study we have compared alpha(v)beta3 expression on blood vessels and on cells of melanocytic origin in nevi and in malignant melanoma lesions. In addition we have examined the lesions for expression of the alpha(v) subunit to gain information on the regulation of alpha(v)beta3 expression on endothelial cells and on cells of the melanocyte lineage. alpha(v)beta3 expression on endothelial cells and on melanocytic cells was a relatively sensitive and specific marker for malignant lesions. However, alpha(v)beta3 expression on endothelial cells in primary melanoma lesions was not associated with the prognosis of the disease. The alpha(v) subunit and the alpha(v)beta3 complex were differentially expressed on endothelial cells and on melanocytic cells, implying that different regulatory pathways control their expression. This finding may account for the differential clinical significance of alpha(v)beta3 expression on tumor vasculature and on melanoma cells we observed in our patient cohort. Lastly, alpha(v)beta3 may be a useful target for immunotherapeutic approaches in melanoma because of its high expression on the vasculature of all metastatic lesions tested and its restricted distribution in normal tissues.