Purpose: Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non-ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML. Patients and Methods Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m2 continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m2 IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m2 IV over 30 minutes once per day on days 1 to 3 (D + C arm). Results The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A +C arm and 13% and 21% in D + C arm, respectively. Conclusion Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML.