Abstract Hypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated for patients treated with intensive therapy. In this study, we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3–internal tandem duplication mutations), and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), and 54 (34%) patients to the higher, intermediate, and lower-benefit groups, respectively. The overall response rate was 71% (86%, 54%, and 59% in the higher, intermediate, and lower-benefit groups, respectively). The median overall survival (OS) and event-free survival (EFS) times were 30 and 19 months, respectively, in the higher-benefit group; 12 and 8 months in the intermediate-benefit group; and 5 and 4 months in the lower-benefit group (P < .001). The C-index for OS and EFS was higher when stratifying patients according to mPRS classification than with the ELN 2022 classification. The 2-year cumulative incidence of relapse was 35%, 70%, and 60% in the higher, intermediate, and lower-benefit groups, respectively (P = .005). The mPRS classification accurately segregated groups of patients with AML treated with HMA plus Ven. In these patients, N/KRAS and TP53 mutations appear to negatively affect outcomes; therefore, new treatment approaches are warranted.