A total of 33 patients (median age, 44 years) with high-grade, adult soft-tissue sarcoma were treated with etoposide given at 600 mg/m2 in a 72-h continuous infusion and ifosfamide given at 1500 mg/m2 per day for 3 days every 3 weeks. Dose escalation/reduction was protocolled depending on the level of hematological toxicity observed in the preceding course. Overall, 90% of patients had metastatic disease, and the most common histologies were malignant fibrous histiocytoma and leiomyosarcoma. A median of 5 (range, 1-9) courses were given. Of 30 patients who were evaluable for response, 12 (40%) obtained a partial remission, and the median time to progression was 8 (range, 4-13) months. Grade 3-4 leukopenia and thrombocytopenia were seen after 89% and 8% of the courses, respectively; neutropenic fever was seen in half of the patients (15% of courses); and 32% of courses had to be postponed by 7 days or more due to myelosuppression. Dose reduction to below the standard had to be performed in 46% of courses, and dose escalation was achieved in only 13%. The reduced toxicity seen after the addition of granulocyte colony-stimulating factor (G-CSF) in five patients indicates that growth-factor support may enhance the dose intensity of the regimen. The results indicate significant activity for this regimen in adult soft-tissue sarcoma, which may in part be a result of the escalated dose and prolonged mode of administration of the phase-specific agent etoposide. As a result of this pilot series, a phase II study with ifosfamide, etoposide, and G-CSF in advanced adult soft-tissue sarcoma has been initiated by the Scandinavian Sarcoma Group.