Background: KMT2A rearrangements are major genetic entities in the classification of acute myeloid leukemias (AMLs), but their diverse and frequently cryptic nature makes their detection and characterization challenging. Karyotypic anomalies at the KMT2A locus and/or abnormal KMT2A Fluorescence in situ hybridization (FISH) results strongly indicate a KMT2A fusion, but the identification of the translocation partner gene often requires further investigation. KMT2A partial tandem duplications (PTDs), on the other hand, are undetectable by standard cytogenetics methods. Methods: We herein report the optical genome mapping (OGM) analysis of 38 AML samples: 12 cryptic/hard-to-characterize KMT2A fusions, 20 KMT2A-PTDs and 6 cases with no KMT2A anomaly. Results: In all the fusion cases, the rearrangement between 5’KMT2A and the 3’partner gene was identified as a translocation t(v;11q23.3)(v;118479068), and the analysis of co-occurring variants elucidated the formation of the rearrangement. The KMT2A variants detected in the KMT2A-PTD cases were surprisingly diverse. Combined with RNAseq data, OGM analysis identified 9 distinct in-frame KMT2A-PTD variants among the 20 cases analyzed. Conclusions: With the clinical development of menin inhibitors for the treatment of patients with KMT2A-rearranged acute leukemias, the characterization of these rearrangements is of utmost importance. Our results suggest that OGM is a promising tool for accurate genetic diagnosis in this context.