Piperazinedione was administered to 79 patients with solid tumors on an intermittent schedule with single doses of 1.5-36 mg/m2. Courses were usually repeated at 4-week intervals. Twenty-five patients with leukemia were treated at doses of 18-36 mg/m2 (occasionally for 2 successive days) every 1-4 weeks. Of 48 evaluable patients with malignant melanoma, three (6%) achieved partial remission and nine (20%) had stable disease. Eight of 17 (47%) patients with adenocarcinomas and one of two (50%) patients with lymphomas also had stable disease. Six of 14 (43%) patients with acute myelogenous leukemia showed hematologic improvement, as did one of 11 (9%) patients with blast cell crisis of chronic myelogenous leukemia. The principal toxic effect was myelosuppression, which occurred in 69% of the patients with solid tumors. Profound bone marrow aplasia occurred in 19% of the patients, resulting in six deaths (8%). Risk factors for marrow aplasia included extensive prior therapy, prior nitrosoureas, cumulative toxicity from piperazinedione, and abnormal liver function tests. The recommended doses for further studies are 9 mg/m2 for patients with risk factors for marrow aplasia, 12 mg/m2 for patients with prior therapy, 15 mg/m2 for previously untreated patients, and 24-36 mg/m2 for patients with acute leukemia.