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.