The treatment of childhood brain tumors with cerebrospinal fluid (CSF) dissemination is limited by the relative inaccessibility of the CSF to drugs administered systemically and the paucity of available agents for intrathecal therapy. Mafosfamide is a cyclophosphamide derivative, which does not require hepatic activation and thus can be utilized for regional therapy. Between May 1994 and December 1996, 16 patients 2 to 19 (median 12) years old with various disseminated brain tumors were treated with intraventricular mafosfamide via an indwelling subcutaneous reservoir. The patients received mafosfamide at a dose of 20 mg once or twice weekly until remission was achieved, followed by weekly administrations as consolidation therapy, and every 3 to 4 weeks thereafter for maintenance therapy. Except for transient headaches, nausea and vomiting during and immediately after mafosfamide administration no toxicities were observed. Nine of the 16 patients were evaluable for response by CSF cytology. Eight had complete responses and one patient did not respond. In addition to mafosfamide all patients received systemic chemotherapy as well. However, 4 of the 8 responding patients had developed CSF dissemination under concurrent systemic therapy and cleared their CSF only after administration of intrathecal mafosfamide. At a median follow-up of 21 months, 7 patients are in complete and 4 in partial remission, 2 have stable disease and 3 died of tumor progression. We conclude that mafosfamide at a dose of 20 mg can be safely administered into the CSF and may produce responses and prolong remission of the leptomeningeal disease.