The applicability of -internal tandem duplications ( -ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of -ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based -ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant and multiparameter flow cytometry. In 161 patients with de novo -ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment. -ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS). NGS-based -ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of -ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% -ITD MRD 33% no -ITD MRD; < .001) and inferior OS (4-year OS, 31% -ITD MRD 57% no -ITD MRD; < .001). In multivariate analysis, detection of -ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; < .001) and OS (hazard ratio 2.51; = .002). Strikingly, -ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the -ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant detection or multiparameter flow cytometry. NGS-based detection of -ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for -ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.