BACKGROUND: We examined the association between exposure during pregnancy to trihalomethanes, the most common water disinfection by-products, and birth outcomes in a European cohort study (HiWate). We took into account exposure through different water uses, measures of water toxicity, and genetic susceptibility. METHODS: We enrolled 14,005 mothers (2002-2010) and their children from France, Greece, Lithuania, Spain, and the UK. Information on lifestyle- and water-related activities were recorded. We ascertained residential concentrations of trihalomethanes through regulatory records and ad hoc sampling campaigns and estimated route-specific trihalomethane uptake by trimester and for whole pregnancy. We examined single nucleotide polymorphisms and copy number variants in disinfection by-product metabolizing genes in nested case-control studies. RESULTS: Average levels of trihalomethanes ranged from around 10μg/L to above the regulatory limits in the EU of 100 μg/L between centers. There was no association between birth weight and total trihalomethane exposure during pregnancy (beta= 2.2 g in birth weight per 10μg/L of THM, 95%CI -3.3, 7.6). Birthweight was not associated with exposure through different routes or with specific trihalomethane species. Exposure to trihalomethanes was not associated with low birth weight (OR per 10μg/L=1.02, 95%CI 0.95, 1.10), small-for-gestational age (OR=0.99, 0.94, 1.03) and preterm births (OR= 0.98, 0.9, 1.05). We found no gene-environment interactions for mother or child polymorphisms in relation to preterm birth or small-for-gestational age. CONCLUSIONS: In this large European study we found no association between birth outcomes and trihalomethane exposures during pregnancy in the total population or in potentially genetically susceptible subgroups.