Malignant angioendotheliomatosis (MAE) is a lethal intravascular proliferation which has been thought to be of endothelial origin. In order to characterize its cellular nature, we studied 15 cases of MAE immunocytochemically, using antisera for factor VIII-related antigen, cytokeratin, epithelial membrane antigen, vimentin, blood group isoantigens, thoracic duct lining cell antigens (TDLCA), common leukocyte antigen, and Ulex europaeus I lectin. In 14 of 15 cases, common leukocyte antigen was observed in malignant intravascular cells. Similar reactivity for factor VIII-related antigen was present in 14 cases, but was largely restricted to cells enmeshed in fibrin-platelet thrombi, and probably represents adsorption of platelet-derived factor VIII by tumor cells. All cases failed to bind Ulex europaeus lectin and lacked immunoreactivity for TDLCA, cytokeratin, epithelial membrane antigen, and blood group isoantigens; two manifested positivity for vimentin. Immunofluorescent microscopy of frozen tissue in one case showed monoclonal IgM-kappa immunoglobulin on the surfaces of tumor cells. Electron-microscopic study of three cases disclosed a predominant cell type lacking features of epithelial or endothelial differentiation; a minor cell population displayed endothelial characteristics and was thought to be reactive. Four patients with typical MAE also had extravascular large-cell lymphoma in lymph nodes, spleen, adrenal glands, stomach, or soft tissues. Six patients showed clinical evidence of autoimmune disease. These results suggest that MAE displays lymphoid rather than endothelial differentiation.