We evaluated the effect of mitoxantrone (Novantrone; dihydroxyanthracenedione) in the treatment of refractory acute leukemia and acute leukemia in relapse. In this study, 70 patients are currently evaluable. Of the 25 patients who received mitoxantrone 10 mg/m2 X 5, two of 10 with ANLL in relapse, one of five with ALL in relapse achieved complete remission, and one of seven with blastic phase CML responded. At a dose of 12 mg/m2 X 5, nine of 22 patients with ANLL in relapse, one of five patients with blastic phase CML and none of the nine patients with ALL responded. At this dose all remissions occurred after one course of treatment. None of the patients with ANLL or ALL refractory to primary therapy achieved a remission. Toxicities encountered with both dose levels were comparable. However, second courses at 12 mg/m2 X 5 led to severe stomatitis and prolonged cytopenia. We conclude that mitoxantrone is effective therapy for ANLL in relapse and that 12 mg/m2 per day X 5 is the optimal dose schedule. A randomized trial comparing daunorubicin with mitoxantrone in combination with cytarabine in untreated patients with ANLL should answer whether mitoxantrone is less toxic and whether it should replace daunorubicin in standard induction therapy in ANLL.