A randomized study of 264 children and adults with previously untreated localized Ewing's sarcoma of bone was undertaken between 1973 and 1978 by 83 institutions of three national study groups: Children's Cancer Study Group, Southwest Oncology Group, and Cancer and Leukemia Group B. The Intergroup Study was designed to determine if the addition of adriamycin (ADR) or bilateral pulmonary radiotherapy (RT) to vincristine, dactinomycin, and cyclophosphamide (VAC therapy) would improve survival and reduce local recurrences and metastases. All patients received RT to the primary lesion, and the survival rate after 3 years was 65%. The most effective treatment regimen was VAC plus ADR; 74% of the patients were free of disease at 2 years. The lengths of disease-free status and survival of patients treated with VAC plus ADR or VAC plus RT did not differ. However, both regimens were significantly superior to treatment with VAC alone. The addition of ADR or bilateral pulmonary RT to VAC was highly advantageous to patients with nonpelvic primaries. Bone and lung were the major sites of distant relapse, but the addition of bilateral pulmonary RT showed no advantage over that of ADR in reducing the occurrence of lung metastases. These recent results should eliminate some of the pessimism that has accompanied a diagnosis of Ewing's sarcoma, although distant metastases continued to be a major reason for failure in the control of this tumor. Survival of these patients can be improved through well-controlled clinical trials designed to determine optimal adjuvant chemotherapy and treatment of the primary lesion.