Two trials using ifosfamide-based combination chemotherapy for advanced soft-tissue sarcoma have been completed. In the first study, 50 evaluable patients received ifosfamide (5 g/m2) with mesna (5 g/m2) and doxorubicin (40 or 60 mg/m2) intravenously (i.v.) every 3 weeks. In all, 11 patients (22%) achieved an objective response [3 complete responses (CRs) and 8 partial responses (PRs)]. Toxicities included leukopenia, febrile neutropenia, nausea and vomiting, and alopecia. The overall median survival was 12 months. In the second study, 51 evaluable patients received ifosfamide (3 g/m2) with mesna (3 g/m2), both being given i.v. on day 1, together with etoposide (100 mg/m2) infused i.v. daily for 3 days. Six patients (12%) achieved objective responses (1 CR, 5 PRs). Toxicities included leukopenia, nausea and vomiting, and alopecia. The overall median survival was 7.4 months. Neither of these combination regimens appears to be more effective in advanced soft-tissue sarcoma than single-agent therapy with either ifosfamide or doxorubicin. If the results of chemotherapy in the management of these tumors are to be improved a new approach to therapy is clearly required.