Measurable residual disease (MRD) is a strong prognostic factor in acute myeloid leukaemia (AML). Next-generation sequencing (NGS) offers promise but must distinguish true signal from background. We assessed MRD in 98 adult AML patients in first complete remission after intensive chemotherapy using a duplex unique molecular identifier (UMI)-based NGS capture panel. Error reduction analysis showed up to a 20-fold decrease in artefactual calls versus conventional sequencing. Linearity studies with serial dilutions confirmed accurate quantification down to 0.01% variant allele frequency. In this cohort, NGS-MRD positivity did not significantly affect overall survival (OS) or relapse-free survival (RFS) after one course of chemotherapy. However, NGS-MRD positivity >0.1%, excluding DNMT3A, TET2, ASXL1, IDH1 and IDH2 mutations, was significantly associated with inferior outcomes after two courses (OS: hazard ratio [HR] = 3.04, p = 0.0173; RFS: HR = 2.83, p = 0.0097). Combining multiparameter flow cytometry (MFC-MRD) with NGS-MRD identified a double-positive subgroup with particularly poor outcomes after the first course (OS: HR = 7.98, p