Abstract Introduction: Increases in the incidence of both obesity (a risk factor for many adulthood cancers) and acute lymphoblastic leukemia (ALL) in childhood have been observed over the past three decades, thus we sought to identify whether obesity may be an unrecognized risk factor for childhood ALL. Methods: Demographics, anthropometrics and disease characteristics from children and young adults (aged 1-30 years) diagnosed with ALL between 2004-2017 and treated on Children’s Oncology Group (COG) frontline treatment protocols with available pre-treatment anthropometric data (n=4775, AALL17D2) were compared to National Health and Nutrition Examination Survey (NHANES) controls (n=30,107). Individuals were classified as underweight, normal weight, overweight, or obese, per standard CDC age- and sex-based pediatric and adult definitions for body mass index (BMI). Multivariate logistic regressions were performed, adjusting for sex, race/ethnicity, age, socioeconomic status and obesity status, to assess associations between BMI classification and ALL. Additional models were performed stratifying by ALL disease characteristics. Results: ALL patients (72% B-ALL, 28% T-ALL) were more likely to be male (62%), 58% were non-Hispanic white, 9% non-Hispanic black and 24% identified as Hispanic. Among ALL patients, 5% were underweight, 58% normal weight, 17% overweight and 20% obese. Using normal weight as reference, BMI above normal weight classification was associated with ALL diagnosis (overweight, OR=1.10, 95% CI 1.00-1.20, p=0.046; obese, OR=1.15, 95% CI 1.05-1.25, p=0.002), as was underweight (OR=1.74, 95% CI 1.48-2.03, p=<0.0001). When stratified by sex, the associations with overweight and obesity were only observed in males (ptrend<0.0001), and when stratified by ALL immunophenotype, associations with overweight and obesity were only observed in B-ALL (ptrend<0.0001). Obesity was also associated with moderate to high levels of ALL central nervous system (CNS) involvement (CNS2, OR=1.30, 95% CI 1.08-1.57, p=0.006; CNS3, OR=2.28, 95% CI 1.24-4.17, p=0.005). Conclusions: This is the first study, to our knowledge, to show that pre-treatment overweight or obesity is associated with ALL, specifically among males and B-cell immunophenotype. Furthermore, ALL CNS involvement was associated with obesity. This study also confirmed the known association between underweight and ALL. Although the associations between BMI status and newly diagnosed ALL may be secondary to detrimental physiologic effects of ALL (i.e. underweight at time of diagnosis), they also suggest a role for inflammation, environmental exposures, or other genetic susceptibility in ALL pathogenesis. Further analyses are needed to elucidate whether other ALL disease characteristics, such as cytogenetics, may be associated with pre-treatment childhood BMI. Citation Format: Taumoha Ghosh, Michaela Richardson, Justin Ryder, Logan Spector, Lucie Turcotte. Obesity as a risk factor for pediatric acute lymphoblastic leukemia: A report from the Children's Oncology Group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3118.