Mutations in TP53 underlie the development of malignant peripheral nerve sheath tumors (MPNSTs) in animal models, but there is controversy regarding the extent of TP53 mutations in human MPNSTs. We assessed the TP53 mutation frequency in 145 consecutive cases from our department over 36 years; 88 cases were histologically confirmed as MPNSTs, and corresponding clinical data were reviewed. Mutation analysis of TP53 Exons 4 to 9 on DNA from formalin-fixed, paraffin-embedded specimens was performed by bidirectional DNA sequencing. Tumors were localized in the extremities (n = 34), trunk (n = 34), or head and neck (n = 20). A minority of patients (n = 26, 30%) had neurofibromatosis type 1 (NF1); in these patients, the diagnosis of MPNST was made at younger ages (33 [SD, 3.6] years vs 49 [SD, 2.9] years in NF1 vs non-NF1; p = 0.003). High p53 protein expression was detected in 18 (21%) of 86 cases by immunohistochemistry. TP53 mutations were detected in 17 (24%) of 72 evaluable tumors, of which 36% were from NF1 patients. TP53 mutation and strong p53 immunostaining were positively correlated (p = 0.002); high proliferation indices correlated with cellular epithelioid and storiform growth patterns. These results indicate that TP53 mutations are relatively rare in human MPNST and that they are not positively correlated with the presence of NF1.