Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared 2 induction regimens in newly diagnosed patients ages 18 to 65 with acute myeloid leukemia (AML)/high-risk myelodysplastic syndromes, that is, idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m2 on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event-free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. We randomized 402 and 393 evaluable patients to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% vs 75% after cycle I). Clofarabine added grades 3 to 4 toxicities and delayed hematological recovery. At a median follow-up of 36 months, the study revealsnodifferences in overall survivalandEFSbetweenthe control (EFS,35%63 [standard error] at 4 years) and clofarabine treatments (38% ± 3) but a markedly reduced relapse rate (44% ± 3 vs 35% ± 3) in favor of clofarabine and an increased death probability in remission (15%±2 vs 22%±3). In the subgroup analyses, clofarabine improved overall survival and EFS for European Leukemia Net (ELN) 2010 intermediate I prognostic riskAML(EFS,26%64 vs40%65 at 4 years;CoxP5.002) and for the intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% 6 5 vs 40% 6 7; Cox P < .001). Clofarabine improves survival in subsets of intermediate-risk AML only. HOVON-102 study is registered at Netherlands Trial Registry #NTR2187.