Sixteen patients who developed CT or MRI scan evidence of recurrent diffuse astrocytoma after radiation therapy and nitrosourea-containing chemotherapy received ifosfamide (2500 mg/m2/day for 3 consecutive days) and mesna (500 mg/m2/dose, 5 doses/day for 3 consecutive days). Toxicity consisted primarily of leukopenia in that 60 percent of patients developed leukocyte nadirs less than 1500/mcL. Excessive somnolence occurred in three patients and may have contributed to a case of fatal pneumonia in one patient but was reversible in the other two. No patient had CT or MRI scan evidence of tumor regression. One patient remains stable at 11.3 + months, but all other patients developed evidence of progressive disease less than 6 months from initiation of therapy. The median times to tumor progression and death were 2.0 and 4.8 months, respectively. In conclusion, while ifosfamide and mesna can be given safely at this dose and schedule, there is no evidence of antitumor effect. The degree of leukopenia observed likely would prevent further dose escalation of ifosfamide or addition of other myelosuppressive agents without additional means of bone marrow support in this population of patients.