Malignant fibrous histiocytoma (MFH) and malignant melanoma (MM) occur together often in the differential diagnosis of poorly differentiated neoplasms. They differ, however, in their biologic behavior and recommended treatment. Investigators have therefore explored a variety of special techniques, including electron microscopy (EM) and immunoperoxidase (IP), to classify these tumors accurately and to separate them from each other. To determine the usefulness of IP and EM in the classification of these tumors, we applied a Fontana-Masson stain and IP probes for vimentin, alpha-1-antitrypsin (alpha-1-A), human melanoma black (HMB)-45, and S-100 protein to twelve MMs and nine MFHs, all of which had available EM studies. Three of twelve MMs were amelanotic. All tumors contained vimentin. Eight of twelve MMs and six of nine MFHs contained alpha-1-A. Ten of twelve MMs and no MFHs contained HMB-45. Eleven of twelve MMs and, surprisingly, two of nine tumors classified by light and EM as MFHs contained S-100 protein. When problems arose with either IP negativity or potentially misleading cross-reactivity, careful EM study allowed definitive classification.