A new classification scheme is proposed for the differential diagnosis of Ewing's sarcoma and malignant peripheral neuroectodermal tumor (MPNT) based on conventional light microscopic and immunohistochemical findings. The presence of Homer-Wright rosettes and/or the expression of at least two neural markers is diagnostic of MPNT Ewing's sarcoma. Ewing's sarcoma was diagnosed in cases lacking Homer-Wright rosettes and expressing no neural marker or only one in immunohistochemistry. Using this "new" approach considerable differences were found between both tumor types. Although most MPNT were located in the thoracopulmonary region, Ewing's sarcoma was located predominantly in the pelvis and extremities. The mean age of MPNT patients was greater than that of Ewing's sarcoma patients. Most importantly, however, was a statistically significant difference in prognosis: disease-free survival in Ewing's sarcoma patients at 7.5 years follow-up was 60% compared with 45% MPNT patients (P = 0.026). The detection of HNK-1 in MPNT indicated a more aggressive biologic behavior, and the expression of protein S-100 appeared to be correlated with a more favorable clinical course.