Two Pediatric Intergroup Ewing's Sarcoma studies of patients with metastatic disease (IESS-MD) have used multimodal therapy consisting of intensive combination chemotherapy and radiation therapy (XRT) to areas of gross disease detected at the time of diagnosis. In IESS-MD-I, conducted from 1975 to 1977, 53 eligible patients were entered and received the chemotherapeutic agents vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and dactinomycin with concomitant XRT (VACA + XRT). In IESS-MD-II, conducted from 1980 to 1983, 69 eligible patients were entered and received 5-fluorouracil (5FU) in addition to the chemotherapeutic agents of IESS-MD-I; initial intensive chemotherapy was given and XRT was delayed until week 10 (VACA + 5FU, delayed XRT). The best response rate (complete and partial remissions combined) was 73% in IESS-MD-I and 70% in IESS-MD-II, so there was no statistical evidence of a difference in response rates (P = 0.62). The length of best response also was similar between studies (P = 0.79), with approximately 30% of the patients on both studies remaining in remission at 3 years. The percentage of patients surviving 5 years or more was 30 on the first study and 28 on the second study (P = 0.49). The major sites of relapse after a response were lung and bone, each occurring with nearly equal frequency. The age of the patient was related to both best response rate and survival: patients 10 years of age or younger had substantially higher response and survival rates than patients 11 years of age or older. The favorable prognosis for younger patients might be explained by a more favorable distribution of primary sites at diagnosis; 39% of patients 10 years of age or younger had rib primary sites, compared with only 16% for patients older than 10 years of age (P = 0.05). The frequency of life-threatening toxicity was substantially higher in IESS-MD-I (30%) than in IESS-MD-II (9%), but the frequency of fatal toxicity was similar (6% to 7%). Fatal complications included Adriamycin-induced cardiomyopathy, Pneumocystis carinii pneumonia, unspecified pneumonitis, and sepsis. The most common toxicity and complications were leukopenia and infections.