Children with Down syndrome, due to their heightened risk of leukemia and increased prevalence of congenital abnormalities, comprise a valuable population in which to study etiology. A Children's Oncology Group study investigated the causes of childhood leukemia in children with Down syndrome diagnosed at ages 0 to 19 years during the period 1997-2002. Telephone interviews were completed with mothers of 158 cases [n = 97 acute lymphoblastic leukemia (ALL) and n = 61 acute myeloid leukemia (AML)] and 173 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed via unconditional logistic regression to evaluate the association between congenital abnormalities and acute leukemia overall, and ALL and AML analyzed separately. The results do not provide evidence for an association among the index children (OR Combined, 0.74; 95% CI, 0.45-1.23; ORALL, 0.67; 95% CI, 0.38-1.20; ORAML,1.03; 95% CI, 0.49-2.16) or their siblings (OR Combined, 1.23; 95% CI, 0.71-2.13; ORALL, 1.12; 95% CI, 0.60-2.09; ORAML, 1.60; 95% CI, 0.66-3.86), suggesting congenital malformations do not confer additional risk of leukemia beyond the risk attributable to trisomy 21 in this population.