BACKGROUND: Acute myeloid leukemia (AML) with RAM immunophenotype is a newly recognized high-risk AML immunophenotypic subcategory characterized by blasts with bright expression of CD56 and weak to absent expression of CD45, HLA-DR, and CD38, as first described by the Children's Oncology Group (COG). The relationship between AML-RAM and other CD56-positive acute leukemias is unclear. The goal of this study is to characterize the clinicopathological characteristics of AML with RAM phenotype and compare them with other CD56 co-expressing acute leukemias. METHODS: From a multi-institutional search, we identified a total of 160 CD56+ acute leukemia cases, including AML-RAM ( RESULTS: AML-RAM patients were significantly younger and presented with significantly higher platelet and white blood cell counts and bone marrow (BM) blast percentages when compared to AUL ( CONCLUSION: We find that AML with RAM phenotype occurs primarily in younger ages, with distinct clinicopathological, immunophenotypic, and mutational presentations, and worse prognosis. This diagnosis should be considered in the clinical differential diagnosis of CD56-positive acute leukemias.