Rhabdomyosarcoma (RMS), which affects mainly pediatric patients, is currently classified into 3 major categories: embryonal, alveolar, and pleomorphic. We have identified a distinct variant of RMS that is characterized by epithelioid morphology, reminiscent of poorly differentiated carcinoma or melanoma, for which we propose the designation "epithelioid RMS." We examined the clinicopathologic features of 16 such cases, which were received in consultation between 1991 and 2009. Ten patients were men, and 5 were women (gender was unknown in 1 case), with a median age of 70.5 years (range 14 to 78). Primary anatomic sites were upper extremity (4), lower extremity (2), head and neck (3), trunk (3), hypopharynx (1), and left atrium (1). Two patients presented with nodal metastases (neck and mediastinal) with unknown primary sites. Of the tumors in somatic locations, 10 were intramuscular, and 2 were subcutaneous. Tumor size ranged from 3 to 8.5 cm; the tumors had nodular fleshy cut surfaces, grossly appreciable necrosis, and infiltrative edges. Microscopically, tumors showed sheet-like growth of uniformly sized epithelioid cells with abundant amphophilic-to-eosinophilic cytoplasm, large vesicular nuclei, and frequently prominent nucleoli. Necrosis and infiltration into adjacent structures (such as skeletal muscle or fat) were present in all cases, and mitotic counts were high (median count 23 per 10 high-power fields) with frequent atypical forms. By immunohistochemistry, all tumors showed diffuse desmin expression, and myf-4 immunostaining was diffuse to multifocally positive. S100-protein was absent in all cases. Cytokeratin was negative in 12 cases and very focally positive in 4 cases. Clinical follow-up information was available for 11 cases (median duration 10 mo). Most patients underwent surgical resection with chemotherapy and/or radiation (none with RMS-specific protocols). Two patients had multiple recurrences, and 2 patients developed satellite nodules near the primary lesion. Six patients had regional lymph node metastases, and 6 patients developed distant metastases, most commonly to the lung. So far, 7 patients have died of disease, 5 within 1 year and 2 within 5 years. Epithelioid RMS is a novel morphologically distinct variant of RMS that closely mimics carcinoma or melanoma. It primarily affects older patients, with a male predilection. The clinical course as determined thus far is aggressive.