Twenty-one cases (25 biopsies including 9 frozen biopsies) of Kaposi's sarcoma associated with the acquired immune deficiency syndrome (AIDS) were examined immunohistochemically, lectin-histochemically, and enzyme histochemically to ascertain the histogenesis of the lesion. The Kaposi's sarcomas were histologically subtyped according to a modified Schmid's classification (granulation tissue-like-, angiosarcoma-like- and spindle cell type). In almost all lesions, many atypical vasoforming cells and at least some spindle cells without definite evidence of vasoformation by conventional microscopy were positive for factor VIII-related antigen, BMA 120 (a new monoclonal antibody to an endothelial cell-specific antigen), Ulex europaeus I (UEA-I), alkaline phosphatase and ATPase. Linear reaction products for BMA 120 and UEA-I, suggesting the luminal surface of immature vascular channels, were sometimes recognized in the positive spindle cells. Electron micrographs confirmed endothelial characteristics, such as irregular and fragmented but distinct basal lamina and numerous pinocytotic vesicles, in both the UEA-I- and ATPase-positive spindle cells. Among spindle cells negative for the endothelial markers, there were many macrophages as a stromal reaction to tumor tissue, identified by monoclonal antibodies to macrophages (KiM 6, 7, 8 and EBM 11), acid phosphatase and alpha-naphthyl acetate esterase. The results of the immuno- and enzyme histochemical investigations did not correlate with the different histologic types of Kaposi's sarcoma. However, our results strongly suggest that tumor cells of Kaposi's sarcoma are derived from vascular endothelial cells rather than lymphatic endothelium.