To assess the effect of water chlorination by-products on specific birth defects, the authors conducted a nationwide cross-sectional study of 285,631 Norwegian births in 1993-1998. Risks of birth defects according to four chlorination by-product exposure categories were compared on the basis of chlorination (yes/no) and level of water color (mg Pt/liter), representing the amount of natural organic matter: high (chlorination, < or =20), medium (chlorination, 10-19.9), and low (chlorination, <10) exposure, with no chlorination and low color (<10) as the reference category. In logistic regression analysis, the risks of any birth defect (adjusted odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.01, 1.25) and of cardiac (adjusted OR = 1.37, 95% CI: 1.00, 1.89), respiratory system (adjusted OR = 1.89, 95% CI: 1.00, 3.58), and urinary tract (adjusted OR = 1.46, 95% CI: 1.00, 2.13) defects were significantly associated with exposure (medium and high combined). Regarding risk of specific birth defects, only that for ventricular septal defects was significantly elevated, with an exposure-response pattern, yielding adjusted odds ratios of 1.63 (95% CI: 1.02, 2.58) for the medium and 1.81 (95% CI: 1.05, 3.09) for the high exposure categories. Furthermore, risk of neural tube defects was related to high color (adjusted OR = 2.60, 95% CI: 1.30, 5.26).