We have investigated the prognostic significance of isocitrate dehydrogenase 2 (IDH2) mutations in 1473 younger adult acute myeloid leukemia patients treated in 2 United Kingdom Medical Research Council trials. An IDH2 mutation was present in 148 cases (10%), 80% at R140 and 20% at R172. Patient characteristics and outcome differed markedly between the 2 mutations. IDH2^R140 significantly correlated with nucleophosmin mutations (NPM1^MUT), whereas IDH2^R172 cases generally lacked other molecular mutations. An IDH2^R140 mutation was an independent favorable prognostic factor for relapse (P = .004) and overall survival (P = .008), and there was no significant heterogeneity with regard to NPM1 or FLT3 internal tandem duplication (FLT3/ITD) genotype. Relapse in FLT3/ITD^WTNPM1^MUTIDH2^R140 patients was lower than in favorable-risk cytogenetics patients in the same cohort (20% and 38% at 5 years, respectively). The presence of an IDH2^R172 mutation was associated with a significantly worse outcome than IDH2^R140, and relapse in FLT3/ITD^WTNPM1^WTIDH2^R172 patients was comparable with adverse-risk cytogenetics patients (76% and 72%, respectively).