In a prospective study, 18 evaluable patients with recurrent osteosarcoma were treated with ifosfamide, 1.8 g/m2 daily for 5 consecutive days. Courses were repeated every 4 weeks. Additional mesna (2-mercaptoethane sulfonate) was given to prevent urotoxicity. All patients had measurable lung deposits and all but one had been pretreated with various cytotoxic agents. Six patients (33%) showed therapeutic response, two complete and four partial, with a median duration of 5.5 months (range, 3-47+). Toxicity included myelosuppression, alopecia, nausea, and vomiting. No severe urotoxicity or central nervous system toxicity was observed. Thus, high-dose ifosfamide in combination with mesna seems to be a safe and effective agent for the chemotherapy of osteosarcoma.