Two cases of endovascular papillary angioendothelioma (EPA) of the skin were studied immunohistochemically to assess the expression of endothelial, leukocytic, and epithelial determinants by these lesions. The tumor cells in both cases were labeled by antibodies to Factor VIII-related antigen, vimentin, and blood group isoantigens; they also bound Ulex europaeus I agglutinin. On the other hand, immunoreactivity for epithelial membrane antigen, Leu-M1, HLA-DR (Ia-like antigen), and leukocyte common antigen (LCA) was not observed. Stromal and intravascular lymphocytes were labeled intensely with antibodies to LCA and HLA-DR and were intimately associated with papillary configurations of proliferating intravascular tumor cells. These results confirm the endothelial nature of EPA and suggest that the cells of this lesion may differentiate toward "high" endothelial cells, which have been shown to interact functionally with circulating lymphocytes.