On the basis of ifosfamide's demonstrated single-agent activity in adult soft-tissue sarcoma, the Eastern Cooperative Oncology Group (ECOG) tested whether ifosfamide would add to the efficacy of doxorubicin in a three-regimen, controlled phase III trial. Doxorubicin, ECOG's standard to which newer chemotherapeutic treatments are compared, was given at a dose of 80 mg/m2 every 3 weeks and was designated the control regimen. Ifosfamide was given at a dose of 3,750 mg/m2 on days 1 and 2 every 3 weeks in combination with 30 mg/m2 doxorubicin given each day for 2 days; additionally, mesna was given to counter the genitourinary toxicity associated with ifosfamide. A second experimental regimen consisted of doxorubicin (40 mg/m2), mitomycin (8 mg/m2), and cisplatin (60 mg/m2), all given intravenously on day 1, with repeated cycles being scheduled for day 21. Of the 279 adults with soft-tissue sarcoma who were entered in the study, 260 were analyzed. The overall response rate was 20% for doxorubicin, 34% for ifosfamide/doxorubicin, and 31% for doxorubicin/mitomycin/cisplatin, with the difference between the first two regimens being significant (P = 0.04). The median survival was 8.8, 11.5, and 9 months, respectively, for the three regimens. Myelosuppression, the predominant toxicity, occurred in 60%, 88%, and 58% of patients, respectively.