Biallelic mutations of the CEBPA gene (CEBPA ^bi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPA ^sm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPA ^sm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPA ^bi and 109 CEBPA ^sm (60 affecting the N-terminal transactivation domains [CEBPA ^smTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPA ^smbZIP]). Interestingly, patients carrying CEBPA ^bi or CEBPA ^smbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 10 ⁹/L and 35.7 × 10 ⁹/L) than patients with CEBPA ^smTAD (median age, 63 years, median WBC 13.1 × 10 ⁹/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPA ^bi; 36.7% CEBPA ^smbZIP vs 6.7% CEBPA ^smTAD; P < .001) or NPM1 mutations (3.1% CEBPA ^bi; 8.2% CEBPA ^smbZIP vs 38.3% CEBPA ^smTAD; P < .001). CEBPA ^bi and CEBPA ^smbZIP, but not CEBPA ^smTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPA ^bZIP-inf). When patients were classified according to CEBPA ^bZIP-inf and CEBPA ^other (including CEBPA ^smTAD and non-CEBPA ^bZIP-inf), only patients bearing CEBPA ^bZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.