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The negative prognostic impact of internal tandem duplication of FLT3(FLT3-ITD) in patients with acute myeloid leukemia with mutated NPM1(AML-NPM1) is restricted to those with a higher FLT3-ITD allelic ratio (FLT3high; ≥0.5) and considered negligible in those with a wild-type (FLT3WT)/low ITD ratio (FLT3low). Because the comutation of DNMT3A(DNMT3Amut) has been suggested to negatively influence prognosis in AML-NPM1, we analyzed the impact of DNMT3Amutin FLT3-ITD subsets (absent, low, and high ratios). A total of 164 patients diagnosed with AML-NPM1included in 2 consecutive CETLAM protocols and with DNMT3Aand FLT3status available were studied. Overall, DNMT3Amutstatus did not have a prognostic impact, with comparable overall survival (P= .2). Prognostic stratification established by FLT3-ITD (FLT3WT= FLT3low>FLT3high) was independent of DNMT3Amutstatus. Measurable residual disease (MRD) based on NPM1quantitative polymerase chain reaction was available for 94 patients. DNMT3Amutwas associated with a higher number of mutated NPM1transcripts after induction (P= .012) and first consolidation (C1; P< .001). All DNMT3Amutpatients were MRD+after C1 (P< .001) and exhibited significant MRD persistence after C2 and C3 (MRD+vs MRD−; P= .027 and P= .001, respectively). Finally, DNMT3Amutpatients exhibited a trend toward greater risk of molecular relapse (P= .054). In conclusion, DNMT3Amutdid not modify the overall prognosis exerted by FLT3-ITD in AML-NPM1despite delayed MRD clearance, possibly because of MRD-driven preemptive intervention.