To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia. Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m(2)/d for 7 days or 200 mg/m(2)/d for 9 days. Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment. Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.