The objective of this study was to examine whether H2 blockers represent a major teratogenic risk. This prospective cohort study was done at the Motherisk Program, a Teratology Information Service, Toronto, Canada. The subjects included 178 women who contacted Motherisk about gestational H2-blocker use, and 178 controls matched for maternal age, smoking, and heavy alcohol consumption. The main outcome measures were primary--major malformations, and secondary--pregnancy outcome, method of delivery, gestational age, prematurity, birthweight, small for gestational age infants, neonatal health problems, and developmental milestones. No increase in major malformations was found following first trimester exposure to H2 blockers [2.1% vs 3.5% (controls), mean difference (95% CI) -1.4% (-5.2, +2.4)]. No other aspects of pregnancy outcome or neonatal health differed between groups. This study suggests that H2-blocker exposure during the first trimester does not represent a major teratogenic risk.