The clinical role of vascularity was examined in metastatic melanoma, analyzing the correlation of the blood vessel density and prognosis. Our study included 51 specimens of metastatic melanoma tissue samples from 31 patients treated with combined chemo-immunotherapy. PECAM-1 (CD31) was used for assessing vascularity by immunohistochemical staining. On the basis of blood vessel counts, patients were classified into 2 main groups: low and high vascularity. A higher blood vessel density was found to be associated with shorter survival, estimated from the primary diagnosis of the disease (38 months), compared with patients with low blood vessel counts (68 months). A similar tendency was observed when vascularity was correlated to the survival period after the detection of the first metastases (13 vs. 30 months) and with survival since the initiation of chemo-immunotherapy (8 vs. 16 months). When vascularity and some common prognostic factors, such as age, sex, DNA ploidy and WHO tumor response, were used for a Cox multivariate analysis, vascularity turned out to be the most significant independent prognostic factor. Our results suggest that counting the blood vessels identified by immunohistochemical staining for the endothelial cell-specific CD31 is a powerful predictor for prognosis in patients with metastatic melanoma and should be considered when selecting patients for therapy.