Venetoclax plus hypomethylating agents are considered standard of care for patients with acute myeloid leukemia (AML) judged ineligible for intensive chemotherapy (IC). Real-world studies complement clinical trials, because patterns of patient selection, treatment exposure, and postremission management may vary. This prospective observational multicenter study included 209 newly diagnosed IC-ineligible patients with a median age 75 years (interquartile range, 71-81 years). A high proportion of patients had secondary AML (53.7%), adverse-risk disease (35.3%), and complex karyotype (15.5%). At a median follow-up of 22.5 months (range, 0.1-43), median overall survival (mOS) was 11.7 months (95% confidence interval [CI], 9.9,15.4). Composite complete remission was achieved in 65.2% (CR, 44.4%; CR with incomplete hematologic recovery, 20.8%). Of responding patients, 21.1% underwent stem cell transplantation. When stratified based on VIALE-A original eligibility criteria, mOS was 17.8 months for patients meeting eligibility criteria and 10.7 months for patients who did not (P = .027). AML ontogeny (P = .024), reduced kidney function (P = .001), Charlson Comorbidity Index (CCI; P = .0017), European LeukemiaNET (ELN) risk (P = .01), and body mass index (P = .0298) were significantly associated with OS. Multivariant Cox regression analysis confirmed independent association of OS with AML ontogeny (P = .012), CCI (P = .033), and ELN risk (P = .019). Patients enrolled in the latter half of the study period demonstrated improved OS than those enrolled earlier (P = .026). This prospective observational study highlights outcomes of patient subgroups, including those excluded from registration trials. This trial was registered at www.clinicaltrials.gov as #NCT03987958.