An accurate histopathologic diagnosis is essential for an adequate treatment of soft tissue sarcomas. The diagnosis of malignant peripheral nerve sheath tumor (MPNST) can be complex, particularly outside the neurofibromatosis type 1 (NF1) context. MPNST is a rare malignancy, and due to the lack of specific histologic criteria, several differential diagnoses must be considered. A total of 350 patients diagnosed with MPNST (from 1990 to 2013) were retrieved from the French sarcoma network (RRePS) and the Conticabase (Connective Tissue Cancer Network database). Tumor samples were available for 160 cases (45.2%). Pathology review, immunohistochemistry (IHC), and molecular analysis (when dealing with a monomorphic sarcoma) were systematically performed. Patient, tumor, and treatment characteristics were evaluated to identify prognostic factors for the definitive primary MPNST (n=106) cohort. Twenty-nine tumors (18.1%) initially diagnosed as MPNST were reclassified on the basis of histologic review, IHC, and molecular analysis. Patients with NF1 disease comprised 64% of the remaining cohort. The 5-year overall survival for patients from the entire cohort was 47%, 34.8% for NF1 patients, and 68.5% for patients without NF1 disease, making NF1 syndrome an independent poor prognostic factor of survival. Positive margins and lack of radiation therapy were independent predictors of local recurrence. The Fédération Nationale des Centres de Lutte Contre le Cancer tumor grade was an independent prognostic indicator of metastasis. Given the therapeutic implications of a misdiagnosis, the systematic pathology review, IHC, and molecular analysis (when dealing with monomorphic sarcoma) strategy allowed reclassification of 20% of cases, mainly the sporadic MPNSTs.