There are still many uncertainties regarding the risk of adverse pregnancy outcomes associated with exposure to drinking water disinfection by-products. In Montréal, Québec, Canada, we carried out a hospital-based case-control study including 493 cases of intrauterine growth restriction defined as birth weight below the 10th percentile for gestational age and sex, according to Canadian standards. Controls were babies (n = 472) delivered at the same hospital whose birth weight was at or above the 10th percentile, matched for gestational age, race, and sex. Exposure to total and specific trihalomethanes was measured using regulatory data collected by municipalities and the provincial Ministry of Environment. Residential history, water drinking, and shower habits during pregnancy, as well as known risk factors for intrauterine growth restriction, were measured with a face-to-face interview with all mothers. Mothers and newborns were characterized for two genetic polymorphisms, one in the CYP2E1 gene (G1259C), and another in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T). Exposure to specific and total trihalomethanes from drinking water, determined for 458 cases and 426 controls, did not result in an increased risk of intrauterine growth restriction. However, significant effect modification was observed between newborns with and without the CYP2E1 variant; among newborns with the variant, the adjusted odds ratio for intrauterine growth restriction associated with exposure to average total trihalomethanes above the 90th percentile (corresponding to 29.4 microg/L) was 13.20 (95% confidence interval, 1.19-146.72). These findings suggest that exposure to trihalomethanes at the highest levels can affect fetal growth but only in genetically susceptible newborns.