Malignant peripheral nerve sheath tumor (MPNST) commonly presents a diagnostic challenge and may resemble a variety of other soft tissue neoplasms microscopically. The authors have examined 62 examples of MPNST immunohistochemically, using antibodies to S-100 protein, myelin basic protein (MBP), and Leu-7, all of which are potential neural markers. Sixty-eight percent of all cases expressed at least one of these three determinants, representing a higher rate of immunoreactivity than that seen for single nervous system antigens in previous studies. Conjoint reactivity for S-100/Leu-7, S-100/MBP, and MBP/Leu-7 was seen in 34%, 34%, and 24% of cases, respectively. This coexpression of antigens is important, because none of them in isolation is immunospecific for nerve sheath tumors. In addition, stains for epithelial membrane antigen were reactive in two epithelioid tumors in this series, and eight spindle-cell neoplasms demonstrated desmin positivity. Analyses for cytokeratin, carcinoembryonic antigen, and Factor VIII-related antigen were negative in all cases. These results indicate an overlap between the immunocytochemical attributes of malignant peripheral nerve sheath tumors and other soft tissue sarcomas and emphasize the desirability of assessing multiple neural markers in such cases.