The authors evaluate the efficacy and feasibility of dose-intensive doxorubicin and ifosfamide combination chemotherapy in patients with sarcomas. From January 1995 to April 1996, 33 evaluable patients with either metastatic sarcoma or primary sarcomas with a high-risk for metastases (all except one was previously untreated with chemotherapy) were treated on two consecutive protocols. The median age was 45 years (range, 15-68 years). The first protocol included doxorubicin at 75 mg/m2 given as a 72-hour infusion on days 1 to 3 along with ifosfamide at 2 g/m2/d over 2 hours x 5, days 1 to 5 (protocol AI 75/10). Granulocyte colony-stimulating factor (G-CSF) was used only if indicated according to American Society of Clinical Oncology guidelines. The second protocol included doxorubicin at 90 mg/m2 as a 72-hour continuous infusion and ifosfamide at 2.5 g/m2/d for 4 days (protocol AI 90/10) with prophylactic G-CSF. A median of four cycles were administered (range, 1-6). Three patients achieved a pathologic complete response (CR) and 18 patients achieved a partial response (PR) for a response rate (RR) of 64% (95% confidence interval (CI), 45-80%). Response rate for the subset of patients with soft-tissue sarcomas was 66% (95% CI, 46-82%). Only three patients progressed on therapy. Febrile neutropenia was noted in 31% of cycles at AI 75/10 and in 56% of cycles at AI 90/10. One patient developed reversible grade 3 central nervous system (CNS) toxicity. There was one treatment-related death on AI 90/10 secondary to doxorubicin cardiac toxicity at a cumulative dose of 435 mg/m2. Dose-intensive doxorubicin plus ifosfamide is feasible in appropriately selected patients and appears to be a very active regimen in patients with sarcomas. The authors are currently testing this regimen with G-CSF and thrombopoietin.