More than 50% of infants with Down syndrome have associated defects that cause considerable morbidity and mortality. We evaluated the hypothesis that the trisomic genome interacts with environmental factors to increase the risk for specific associated defects. We evaluated risk factors present during early pregnancy in a multiracial population of 687 infants with Down syndrome. Mother's cigarette smoking was associated with the grouped cardiac defects [odds ratio (OR) = 2.0; 95% confidence interval (CI) = 1.2–3.2). When adjusted for other cardiac defects and maternal race, the following specific defects were associated with smoking: atrioventricular canal (OR = 2.3; 95% CI = 1.2–4.5), tetralogy of Fallot (OR = 4.6; 95% CI = 1.2–17.0), and atrial septal defects without ventricular septal defect (OR = 2.2; 95% CI = 1.1–4.3). Hirschsprung disease was associated with mother's daily consumption of more than three cups of coffee (OR = 6.02; 95% CI = 1.2–29.7) and with mother's fever (OR = 3.4; 95% CI = 0.7–16.4), but the number of cases was small. Use of alcohol was not associated with any defect. Mother's race, age, parity, income, or education did not confound the associations. Results suggest that environmental factors can modify the occurrence of associated anomalies in the embryo with Down syndrome. (Epidemiology 1999;10:264–270)