Twenty-nine cases of malignant schwannoma consisted of three groups; 11 tumors associated with von Recklinghausen's disease (group I), nine tumors arising grossly from nerve trunks (group II), and 11 tumors so diagnosed basically on the histologic features (group III). Using the immunoperoxidase methods, the tumors were investigated with regard to S-100 protein, keratin, and epithelial membrane antigen (EMA). Approximately one-third of the cases (10 of 29) were devoid of S-100 positive cells and the remaining two-thirds (19 of 29) contained positive cells, with variable frequencies. The number of S-100 positive cells differed, depending largely on the presence or absence of neurofibroma-like areas in the tumor. The positive cells were rarely found in the group III tumors, which were neither associated with von Recklinghausen's disease nor connected to nerve trunks, even when their histologic features were unequivocal. Certain specific organoid structures in the tumor, such as neuroid or tactoid ones, were positive for S-100 protein. In one of the two malignant epithelioid schwannomas, the tumor cells were strongly positive for S-100 protein, thereby suggesting melanocytic differentiation. This tumor was interpreted as a melanocytic malignant schwannoma rather than a malignant melanoma, based in part on the fact that the overlying epidermis was uninvolved in this patient with von Recklinghausen's disease. True epithelial differentiation in one case of glandular schwannoma was verified by the positive stain of EMA along the inner surface of the glandular element.