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To confirm the previously reported increased risk of leukemia among macrosomic children (those with birth weight >4 kg).Birth certificates of Arizona, Illinois, and Kentucky children diagnosed as having acute lymphoblastic leukemia (ALL) before age 5 years were matched with birth certificates from leukemia-free children of the same sex, race, and ethnicity who were born in the same county on or about the same day. Odds ratios (ORs) for ALL among children of low (<2.5 kg) or high (>4 kg) birth weight were calculated by conditional logistic regression.Children with high birth weight had an elevated risk of ALL in the first 5 years of life (OR 1.28, 95% confidence interval [CI] 1.01–1.61). The excess risk was confined to non-Hispanic whites (OR 1.77, 95% CI 1.27–2.48), both boys (OR 1.57, 95% CI 1.01–2.45) and girls (OR 2.10, 95% CI 1.26–3.52).This study confirms the association between high birth weight and ALL previously reported by other studies in children of European ancestry. The literature on maternal risk factors for both macrosomia and ALL is reviewed, with maternal overnutrition emerging as a plausible risk factor for both outcomes.