Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Continuous oral low-dose chemotherapy with methotrexate (MTX) and cyclophosphamide (CPM) has modest activity in heavily pretreated patients with breast cancer. We explored the efficacy of 100 mg CPM daily and 5 mg MTX twice weekly in relapsed glioblastoma. Ten patients, 22-59 years old, with a Karnofsky score of 50% or higher who had failed at least two chemotherapies were accrued. No toxicity was observed. No patient showed a complete or partial response. Five of 10 patients progressed within 2 months of therapy. Another five patients progressed after 3-4.5 months. The median time to progression was 2.5 months. The median overall survival after start of MTX/CPM was 6.9 months (range 0.5-18.8 months). Since the progression-free survival rate at 6 months was 0%, the trial was prematurely closed.