BACKGROUND Patients with high grade soft tissue sarcoma greater than or equal to 10 cm have a 3-year disease-free survival of approximately 30%. There is no convincing evidence, however, that postoperative adjuvant chemotherapy is beneficial. Preoperative chemotherapy has theoretical advantages over postoperative chemotherapy. METHODS Twenty-nine evaluable patients with primary or recurrent high grade, nonmetastatic, soft tissue sarcoma were treated with two preoperative cycles of cyclophosphamide 500 mg/m2, doxorubicin 60 mg/m2, and DTIC 1000 mg/m2 before definitive surgery and radiation. Clinical and radiologic assessment of response to chemotherapy was performed preoperatively, and the resected specimen was examined for treatment effects. Patients who did not progress during preoperative therapy were eligible to receive four additional cycles of chemotherapy. Disease-free and overall survival rates of study patients were compared with two cohorts of historic controls. RESULTS Although subjective changes in the firmness of some tumors were observed, only one patient met the criteria for partial response (3%, 2-sided 95% confidence interval = < 1-17%). Intratumoral hemorrhage, cystic necrosis, and liquefaction were observed regularly, and three tumors were more than 90% necrotic. Toxicity of the chemotherapy was acceptable, but patients were reluctant to receive postoperative therapy. The median time free from distant metastasis was 28 months; median survival was 35 months. These results were not superior to the experience with no chemotherapy, or with postoperative doxorubicin. CONCLUSIONS Adjuvant chemotherapy for patients with soft tissue sarcoma remains investigational. There is a strong rationale, however, for continued investigation of preoperative chemotherapy for high risk patients using doxorubicin and ifosfamide with colony stimulating factor support. Development of sensitive and specific methods to assess response to preoperative chemotherapy is needed.