Our purpose was to investigate the prognostic impact of overweight/obesity in 5-year event-free survival (EFS) in a cohort of children with acute lymphoblastic leukemia (ALL). We retrospectively analyzed 181 newly diagnosed ALL children enrolled between 1990 and 2009 and treated with Berlin-Frankfurt-Munich (BFM) protocols. The majority of children in our cohort were <10 years-old. Our data clearly indicated that overweight/obesity is an independent predictor of relapse risk, mainly in the intermediate- and high-risk groups (HR) of children. These results could be explained by changes in the chemotherapy pharmacokinetics in overweight/obese patients and by the antiapoptotic effects in leukemic cells caused by adipocytes.