Ifosfamide given to 42 patients iv at 2-2.5 g/m2/day X 4 resulted in partial responses in ten of 28 (36%) evaluable patients with adult soft tissue sarcomas, including two of two with chondrosarcoma; none of nine with pediatric sarcomas (Ewing's sarcoma, osteogenic sarcoma, or rhabdomyosarcoma) achieved partial response. All of the pediatric patients had failed to respond to complicated three- to six-drug regimens of up to 18 months in duration. The response rates in patients with and without prior cyclophosphamide (32%; seven responses among 22 patients; and 20%, three responses among 15 patients) were not significantly different, supporting in vitro evidence of a lack of cross-resistance between the two related compounds. Myelosuppression was dose-limiting. Hemorrhagic cystitis was not observed in patients treated with 400-500 mg of mesna iv every 4 hours during ifosfamide treatment. Nausea and vomiting were generally mild or moderate. Alopecia was universal but reversible. Of the first 11 patients, five became somnolent or developed visual hallucinations (during six of the 12 total courses administered to the five patients). Only one patient had two episodes of neurotoxicity. After reduction of the use of iv antiemetics and major narcotics, single episodes of neurotoxicity were seen in five of the next 27 patients. An asymptomatic acidosis developed in most patients, requiring bicarbonate replacement in one. Ifosfamide appears to be active in previously treated patients with sarcomas and should be evaluated in patients with less extensive prior treatment.