The commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including malignant melanomas, depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a dedifferentiated, malignant, highly invasive cellular immunophenotype (CIP) and distant metastases, as aspects of constant neoplastic progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during malignant melanoma (MM) related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 25 MMs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; +3 to +4) of EDG on endothelial cells was demonstrated in all MM cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. MMs, like most mammalian neoplasms, are characterized by extensive neovascularization, and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including MMs. The importance of TGF-beta in all of the various aspects of neoplastic transformation, as well as malignant disease progression should also be studied more extensively in the future.