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Acute leukemia (AL) is the most common type of childhood cancer and has two major subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Historically, studies in this field have pointed out driver somatic mutations with different mechanisms of pathogenesis. Family-based and large-scale high-throughput sequencing studies have recently uncovered several genetic germline variants, indicating an inherited origin. Familial history of cancer (FHC) is associated with an increased risk of both ALL and AML. Herein we explore the excess of hematological malignancies (HM) in first-degree relatives of patients diagnosed under 21 years old and compare rates of FHC between AML and ALL cases. We revisited the registry of the Brazilian group Estudos Multi-Institucionais das Leucemias Infantis (EMiLI) comprised of 89 cancer centers from 2009 to 2019. Socio-demographic, immunomolecular, and self-reported FHC data were collected using a structured questionnaire at the beginning of the follow-up. Descriptive statistics were used to assess the frequency distribution and differences between cases. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals to evaluate the estimated FHC predisposition to AL. From a total of 5,831 samples, 42.6% were from North/Northeast, 35.7% from South/Southeast, and 21.7% from Midwest macroregions. There was a high frequency of cases (p < 0.001) of Non-White ethnicity in North/Northeast and White ethnicity in South/Southeast. B-cell Precursor ALL was more frequent in Midwest, T-cell acute lymphoblastic leukemia in North/Northeast, and AML cases in South/Southeast. Among 3,618 individuals with AL, 472 had a positive FHC (13%). Of these, 96 (20.3%) reported HM as the origin of cancer. We observed a higher odds of having at least one relative with cancer in AML cases compared to ALL (OR 1.36; 95% CI 1.01-1.82; p = 0.040). When considering only first-degree relatives with any type of cancer, the risk was even more considerable for the AML group than ALL (OR 2.92; 95% CI 1.57-5.42; p = 0.001). With a statistical significance value (p= 0.02), we observed that AML cases present higher odds of having a first-degree relative with FHC with hematologic origin than ALL cases (OR 5.71; 95% CI 1.91-17.08). This effect was not observed analyzing second degree-relatives or relatives with non-hematological malignancies. Our findings suggest that AML is more associated with a positive FHC than ALL, particularly when having a first-degree relative with HM. Both genetic and environmental exposure factors could be involved in the AL subtypes epidemiology. Identifying children with a higher risk of AL would be beneficial by performing early targeted cancer screening and improving prevention and surveillance programs. Further genomic studies exploring Brazilian childhood AL cases with FHC are crucial to elucidate the role of genetic background and ancestry as risk factors associated with leukemogenesis. Citation Format: Daniela P. Mendes-de-Almeida, Francianne G. Andrade, Paulo Chagas-Neto, Maria do Perpétuo Socorro S. Carvalho, José C. Córdoba, Marcelo dos S. Souza, Logan G. Spector, Maria S. Pombo-de-Oliveira, Brazilian Collaborative Study of Childhood Leukemia, Acronym EMiLI. Acute leukemia excess in families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 801.