We evaluated concurrent gene mutations, clinical outcome, and gene expression signatures of CCAAT/enhancer binding protein alpha (CEBPA) double mutations (CEBPA^dm) versus single mutations (CEBPA^sm) in 1182 cytogenetically normal acute myeloid leukemia (AML) patients (16-60 years of age). We identified 151 (12.8%) patients with CEBPA mutations (91 CEBPA^dm and 60 CEBPA^sm). The incidence of germline mutations was 7% (5 of 71), including 3 C-terminal mutations. CEBPA^dm patients had a lower frequency of concurrent mutations than CEBPA^sm patients (P < .0001). Both, groups were associated with a favorable outcome compared with CEBPA^wt (5-year overall survival [OS] 63% and 56% vs 39%; P < .0001 and P = .05, respectively). However, in multivariable analysis only CEBPA^dm was a prognostic factor for favorable OS outcome (hazard ratio [HR] 0.36, P < .0001; event-free survival, HR 0.41, P < .0001; relapse-free survival, HR 0.55, P = .001). Outcome in CEBPA^sm is dominated by concurrent NPM1 and/or FLT3 internal tandem duplication mutations. Unsupervised and supervised GEP analyses showed that CEBPA^dm AML (n = 42), but not CEBPA^sm AML (n = 18), expressed a unique gene signature. A 25-probe set prediction signature for CEBPA^dm AML showed 100% sensitivity and specificity. Based on these findings, we propose that CEBPA^dm should be clearly defined from CEBPA^sm AML and considered as a separate entity in the classification of AML.