Vascular endothelial cells are specialized mesenchyme-derived epithelial-like lining cells which are the essential participants in benign and malignant vascular tumors. Although endothelia in lower animals often express keratins (K), human endothelia are generally K negative and vimentin-positive. However, K expression has been noted in some endothelia and in some epithelioid vascular tumors. In this study, we systematically examined normal human vascular endothelia and a spectrum of human vascular tumors (n = minimum of 137 tumors with each marker) for simple epithelial keratin polypeptides of the Moll catalogue (K7, K8, K18, and K19). Selected vascular tumors were also evaluated with antibodies to K14 and the monoclonal antibody 34betaE12 that recognizes several keratins of stratified epithelia. Endothelia of normal veins, venules, and lymphatics commonly exhibited focal positivity for K7 and K18, whereas K8, K14, and K19 were not seen in non-neoplastic endothelia with the antibodies used. Lymphangiomas (6 of 7) and venous hemangiomas (6 of 13) often showed K7-positive endothelial cells; K18 was detected less commonly, whereas K8 and K19 were not detected. Epithelioid hemangioendotheliomas (EHEs) showed K7 and K18 expression in the majority of cases (50% and 100%, respectively), while K8 was seen in 10% cases and K14 and K19 in none. In contrast, epithelioid angiosarcomas (EAs) were often positive for K8 and K18 (approximately 50%), whereas they less commonly showed K7 and only occasionally K19; all tumors were negative for K14 and with the antibody 34betaE12. Nonepithelioid angiosarcomas (AS) less commonly showed keratin expression with K7, K8, and K18 being positive in 20% of cases, and K14 and K19 in none of the cases. Epithelial membrane antigen (EMA) was occasionally detectable in EHE (2/19) but was present in 4 of 16 (25%) EAs and 17 of 48 (35%) nonepithelioid AS. These findings document the common presence of focal reactivity for K7 and K18 in subsets of normal endothelia and also the frequent presence of simple epithelial keratins in malignant vascular tumors, while such expression is uncommon in nonepithelioid angiosarcomas. K- and EMA-positivity in neoplastic endothelia needs to be considered in the evaluation of human tumors. K antibodies such as those specific to K19 or AE1 that do not react with K8 and K18 should be used in the differential diagnosis of epithelioid vascular tumors and carcinomas.