Neoplasms of unknown origin present a difficult diagnostic dilemma, particularly if they are very poorly differentiated. Adenocarcinomas, squamous cell carcinomas, melanomas, lymphomas, and sarcomas can all be very difficult to diagnose if the light microscopic cytomorphology is sufficiently undifferentiated. Electron microscopy (EM) can either demonstrate differentiation or narrow the range of differential diagnoses. The authors report the case of a 64-year-old male who has been HIV positive for several years and was found to have expansile lytic lesions in several ribs and a thumb fracture associated with a soft tissue mass which was biopsied. The tumor was composed of very pleomorphic malignant cells without specific differentiation. The malignant cells stained positive for pancytokeratin (AE 1/3), EMA, CEA, CK20, and CK7. Rare cells had mucicarmine-positive intracytoplasmic droplets. They were negative for S-100, calretinin, CD45, MART-1, and vimentin. EM revealed intracytoplasmic lumina with long microvilli and many well-formed desmosomal junctions. The diagnosis was initially very broad. Immunohistochemistry narrowed the diagnosis to carcinoma, but EM alone was able to narrow the diagnosis to poorly differentiated adenocarcinoma. In a neoplasm of unknown origin, EM can either narrow the differential significantly or, in the case of limited material, provide information that otherwise may not be attainable.