Thirteen patients with relapsed acute leukemia, 12 adults with acute nonlymphocytic leukemia, and one child with acute lymphoblastic leukemia were treated with VP 16-213, an epipodophyllotoxin analog, at a dose of 200-300 mg/m2/day X5 as a 2-hour intravenous infusion. Only four patients achieved bone marrow aplasia and three regenerated with leukemic cells. The fourth patient achieved a partial remission for 4 weeks. Toxicities included myelosuppression (WBC nadir 500/microliter), nausea and vomiting (70% of courses), mucositis (23%), esophagitis (12%), which contributed to death in one patient, hypotension (12%), and transient liver function abnormalities (12%). It is concluded that increasing the dose of VP 16-213 as employed in this study did not increase the therapeutic activity of VP 16-213 for the treatment of relapsed leukemia but did increase the risk of toxicity.