Two treatment regimens for metastatic soft-tissue sarcomas were compared in a randomized trial in the cooperative group setting. Histopathologic diagnosis was affirmed by pathology reference panel review in 72% of the 347 patients. In 21% of patients, the reference panel affirmed the diagnosis of soft-tissue sarcoma but disagreed as to type; 7% of patients were ineligible based upon cell type. Of 298 patients evaluable, measurable tumor regression (partial or complete response) occurred in 17% of patients to doxorubicin (70 mg/m2 intravenously) and 18% of patients to doxorubicin (70 mg/m2 intravenously) and vindesine (3 mg/m2 intravenously), each given every 3 weeks. No difference existed in complete response (4% for doxorubicin, 6% for doxorubicin and vindesine) or median survival (9.4 months for doxorubicin, 9.9 months for doxorubicin and vindesine). Overall, 60% of those patients on doxorubicin and vindesine and 46% on doxorubicin experienced a severe or worse toxicity of treatment (P = 0.01). With greater toxicity and lack of any gains in efficacy, the results do not support use of the combination of doxorubicin and vindesine for metastatic soft-tissue sarcomas.