CD31 has recently been reported as a specific marker of endothelial differentiation among non-hematopoietic human neoplasms. In order to address this contention in particular regard to tumors of the skin and subcutis, the authors undertook a comparative study that surveyed 145 mesenchymal lesions. The antibodies used were directed against CD31 (clone JC/70A) and CD34 (clone My 10), and these were compared with binding of Ulex europaeus I agglutinin (UEA). Proliferations that were included in the category of vascular tumors included cavernous and capillary hemangiomas (17 cases); lymphangiomas (8); epithelioid (“histiocytoid”) hemangiomas (3), papillary endovascular hemangioendothelioma (1), angiosarcoma (7), and Kaposi's sarcoma of the mixed angiomatoid and spindle-cell type (17). CD31-immunoreactivity was observed in 35 of 53 vascular lesions; the neoplastic cells in a single angiosarcoma and the spindle cells in each case of Kaposi's sarcoma (KS) were not labeled. In all of the latter tumors, however, staining for CD31 was identified in the endothelia of angiomatoid areas and non-neoplastic blood vessels. These results compared favorably with those' seen with anti-(T).9H, which decorated 36 of 53 vascular tumors - including S of 17 KS cases - and UEA, which bound to the neoplastic cells of 36 lesions. In contrast, all of 92 non-endothelial tumors included in ibis study (34 nerve sheath tumors [30 benign; 4 malignant]; 39 fibrohistiocytic neoplasms 11 benign; 28 malignant]; 9 smooth muscle tumors [6 benign; 3 malignant]; 7 glomus tumors; and 3 giant cell fibroblastomas) were negative for CD31. UEA labeled 3 non-vascular neoplasms, whereas 38 lesions of that type were CD34-positive. The latter proliferations were benign peripheral nerve sheath tumors, examples of dermatofibrosarcoma protuberans, or glomus tumors. Based on these results, it is concluded that CD31 is a relatively sensitive and specific marker for vascular lesions and that, it is worthy of inclusion in diagnostic antibody panels which are designed to separate endothelial tumors from other neoplasms of the skin.