This prospective phase II clinical trial evaluated the effects of single-dose mitoxantrone (36 mg/m2 on day 1) in combination with continuous infusion intermediate-dose cytarabine plus etoposide in 25 patients with refractory or early relapsed acute myeloid leukemia (AML). We compared the results of our current study with those of a previous phase II trial, which had the same eligibility criteria and chemotherapy schedule except that a conventional divided dose of mitoxantrone (12 mg/m2 on days 1-3) was used. The complete remission (CR) rate was significantly lower with the single-dose mitoxantrone regimen than with the divided-dose regimen (24.0% vs. 51.5%; P=0.034), mainly owing to an increased incidence of hypoplastic deaths. CR duration and overall survival were not significantly different between the two regimens. In conclusion, single-dose mitoxantrone was inferior to conventional divided-dose mitoxantrone for treatment of refractory or early relapsed AML in terms of CR rate.