The few previous studies of hypospadias and smoking have suggested either no association or a reduced risk. This study, which uses data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study, includes data on males born with severe hypospadias (i.e. the urethra opens at the penile shaft, scrotum or perineum) from 1997 to 2000. Non-malformed, liveborn male controls were selected randomly from birth certificates or from birth hospitals. Maternal interviews were completed by telephone with 453 case mothers and 1267 control mothers. Maternal smoking was not associated with hypospadias risk. For example, during the third month of pregnancy, smoking < 0.5 pack/day had an odds ratio (OR) of 1.1 [95% CI 0.6, 1.9]; 0.5 pack/day, 0.6 [0.4, 1.1]; and > or = 1 pack/day, 0.8 [0.4, 1.6]. Exposure to any secondhand smoke at home during the third month of pregnancy showed an OR of 0.6 [95% CI 0.4, 1.0], and exposure at work or school, an OR of 0.7 [0.5, 1.1]. Similar risks were observed for other months during the periconceptional period, and adjustment for several potential confounders did not substantially alter results. This analysis does not confirm a recent report suggesting that maternal smoking is associated with a reduced risk of having offspring with hypospadias.