The accurate immunohistochemical diagnosis of epithelioid angiosarcoma--as distinct from carcinomas and other epithelioid neoplasms--is hindered by the lack of endothelial-selective reagents that are both sensitive and specific. To evaluate the potential utility of an "epithelial-specific" and an "endothelial-selective" monoclonal antibody in this differential diagnosis, B72.3 [anti-TAG 72 (tumor-associated glycoprotein-72)] and My 10 [anti-CD34 (the hematopoietic progenitor cell antigen)] were applied to 14 examples of angiosarcoma (seven with an epithelioid phenotype), nine epithelioid hemangioendotheliomas, and eight capillary hemangiomas, together with antibodies to factor VIII-related antigen (F8rag) and cytokeratin (CK), and the lectin Ulex europaeus I (UEA). The results of these analyses were compared with stains fro B72.3, CD34, and Ck in a variety of other epithelioid soft tissue neoplasms, including four epithelioid sarcomas, three epithelioid malignant peripheral nerve sheath tumors, three alveolar soft part sarcomas, four clear cell sarcomas (malignant melanomas of soft parts), five malignant fibrous histiocytomas, and seven epithelioid leiomyosarcomas. The endothelial phenotype of each vascular tumor was supported by staining for either F8rag or UEA in all examples. Only angiosarcomas were reactive with B72.3, including five of seven epithelioid variants. None was positive for cytokeratin. Four epithelioid angiosarcomas were also reactive for CD34, but so were the majority of epithelioid leiomyosarcomas and at least one example each of all other epithelioid soft tissue tumors, except alveolar soft part sarcoma. In contrast, none of the latter tumor types was reactive with B72.3. These data indicate that anti-CD34 is not specific for endothelial tumors, whereas B72.3 reactivity is selective for epithelioid angiosarcomas. Despite published reports to the contrary, no tumor in this series was reactive for cytokeratin. An immunohistochemical panel that includes antibodies to both cytokeratin and B72.3, in addition to other lineage-selective mesenchymal markers, is useful in the diagnostic recognition of epithelioid soft tissue neoplasms.