Background: We analyzed effects of exposure to magnetic fields on the expression of acute leukemia in children with Down syndrome (who have a 20-fold higher risk of leukemia). Methods: We performed a case–control study that included 42 children with both acute leukemia and Down syndrome as cases and 124 healthy children with Down syndrome as controls. We obtained demographic information concerning the children and took spot measurements of magnetic fields at each residence. Results: The odds ratio for direct measurements of magnetic fields ≥6.00 mG was 3.7 (95% confidence interval = 1.05–13.1). Conclusion: The association between magnetic fields and leukemia in children with Down syndrome suggests the possibility of a causal role for magnetic fields in the etiology of leukemia among a genetically susceptible subgroup of children.