Tandem-duplication mutations of theUBTFgene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8),FLT3-internal tandem duplications (FLT3-ITD),WT1-mutations) and inferior outcome. Due to limited knowledge onUBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis.UBTF-TDs were overall rare (n= 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients withUBTF-TDs had significantly higher rates of +8 (34% vs. 9%),WT1(52% vs. 7%) andFLT3-ITD (50% vs. 20.8%) co-mutations, whereasUBTF-TDs were mutually exclusive with several class-defining lesions such as mutantNPM1, in-frameCEBPAbZIPmutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n= 5) retained theUBTF-TD mutation,UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis,UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority ofUBTF-mutant patients,UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17,p< 0.001], RFS [HR: 1.59; 95% CI 1.02–2.46,p= 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49,p= 0.020]). In summary,UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.