Increased maternal body mass index, maternal smoking, and alcohol exposure during pregnancy have been inconsistently reported as potential risk factors for renal birth defects. The low incidence of the most severe renal anomaly, bilateral renal agenesis or hypoplasia (RA/H), has limited the ability to study this fatal defect. Using data from the National Birth Defects Prevention Study, a multicenter case-control study, the authors explored potential relations between RA/H and maternal body mass index, smoking, alcohol, and caffeine exposures. Data available for 75 infants with RA/H born between 1997 and 2003 and for randomly selected control infants without known birth defects (n = 868) were assessed by a model adjusted for folic acid use, all four exposures of interest, and study center. Bilateral RA/H was associated with a body mass index of greater than 30 kg/m(2) prior to pregnancy (adjusted odds ratio (aOR) = 1.92, 95% confidence interval (CI): 1.00, 3.67), smoking during the periconceptional period (aOR = 2.09, 95% CI: 1.08, 4.03), and binge drinking during the second month of pregnancy (aOR = 3.64, 95% CI: 1.19, 11.1). These results support the need for further exploration into the potential mechanisms by which such exposures could interfere with early fetal kidney formation resulting in RA/H.