Immunohistochemical analysis demonstrates expression of cytokeratin AE1/AE3, CD31, ERG, and FLI-1 by most neoplastic cells, with variable focal and weaker immunoreactivity for CAM 5.2, smooth muscle actin, epithelial membrane antigen, and pancytokeratin MNF-116 and no expression of CD34, desmin, and S-100 protein. In contrast to neoplastic cells of epithelioid sarcoma, the plump spindled and rhabdomyoblastic cells of ES-H keep intact their expression of INI-1. The immunoreactivity for CD31, FLI-1, and in particular ERG suggests an endothelial nature of the neoplastic cells. As an ETS family transcription factor, ERG recently has been found to be expressed in endothelial cells, and oncogenic ERG gene fusions occur in subsets of prostatic carcinoma, acute myeloid leukemia, and Ewing sarcoma.9 Immunohistochemical studies have demonstrated that nuclear ERG expression is highly specific for detecting ERG protein in normal endothelia (internal control) and in the endothelial cells of hemangiomas, lymphangiomas, angiosarcomas, epithelioid hemangioendotheliomas, and Kaposi sarcomas. Among nonvascular mesenchymal tumors, only blastic extramedullary myeloid tumors and rare Ewing sarcomas were positive for ERG.Among epithelial tumors, only 50% of prostatic adenocarcinomas showed focal to extensive ERG positivity, with no immunoreactivity in the normal prostate. A large series of other carcinomas and epithelial tumors were negative for ERG.9 On the basis of these observations, ERG may be considered the most specific new marker for normal endothelial cells and proliferating endothelial cells of benign and malignant vascular tumors. Our study is the first to demonstrate strong immunoreactivity for ERG in the nuclei of neoplastic cells of ES-H, further supporting the endothelial nature of the proliferating cells.