We performed an immunohistochemical and ultrastructural study on 67 specimens of malignant fibrous histiocytoma (MFH) from 65 patients. Most of the tumors were musculoskeletal in origin and all presented clinically as a primary malignancy. The tumors were high grade and 57 of 67 were the storiform-pleomorphic subtype. Immunohistochemical studies were performed in 34 cases with both fresh-frozen and formalin-fixed tissue; in 33 cases only formalin-fixed tissue was available. The immunohistochemical panel included vimentin, various molecular weight keratins, epithelial membrane antigen (EMA), desmin, alpha-1-antitrypsin, and alpha-1-antichymotrypsin. Seventeen of 67 (25.4%) cases stained with one or more keratin antibodies. The low molecular weight cytokeratins demonstrated the most widespread and intense staining and, using fresh-frozen tissue, increased sensitivity. Epithelial membrane antigen was detected in 20.6% of cases and six of these cases also stained with keratin. The EMA staining was more focal and less intense than the keratin reactivity. The keratin- or EMA-positive cases were not distinguished by their light microscopic or ultrastructural features. Desmin staining was focally present in 16.9% of cases. The vast majority of tumors stained with vimentin and alpha-1-antitrypsin or alpha-1-antichymotrypsin. There was no staining of tumor cells for S-100. Appropriately fixed tissue was available for electron microscopic evaluation in 15 of 23 MFHs that stained with keratin or EMA. Ultrastructurally, all tumors were composed of an admixture of cells that had the features of fibroblasts, myofibroblasts, and histiocytes; no epithelial structures were identified. This study confirms that MFH may express epithelial markers. It emphasizes the importance of using electron microscopy and clinical findings to distinguish keratin or EMA-positive MFH from carcinoma. This distinction is important because of the significant differences in therapy and prognosis.