Microvessel density (MVD) was estimated in a series of 202 vertical growth phase (VPG) melanomas and 68 corresponding metastases, using a marker for angiogenic endothelial cells (CD105) and Factor-VIII. The expression pattern of vascular endothelial growth factor (VEGF), FLT-1, KDR and thrombospondin-1 (TSP-1) was studied by immunohistochemistry, in situ hybridization and reverse-transcriptase polymerase chain reaction. CD105 stained significantly less vessels, but gave only limited additional prognostic information compared with Factor-VIII, and MVD was an independent prognostic factor for both markers. Ninety-eight percent of all cases showed expression of VEGF, and higher expression was found significantly more frequent in thinner and less vascularized tumors. Possible autocrine loops were suggested by co-expression of VEGF and its two receptors in tumor cells, and by a significant correlation between KDR and tumor cell proliferation (Ki-67) in the subgroup of thicker tumors. Staining of VEGF receptors in endothelium was not correlated with MVD. Strong expression of TSP-1 in tumor stroma was found in 43% of the primary tumors, and was significantly correlated with increased thickness, proliferation and MVD, as well as decreased survival. These data suggest that MVD is associated with prognosis in cutaneous melanomas, and that the VEGF system and particularly TSP-1 seem to be involved in the regulation of angiogenesis and progression of these tumors.