Evidence documenting the safety of acid-suppressing drugs in pregnancy is very limited. The authors assessed the prevalence of congenital malformations in first trimester-exposed pregnancies to cimetidine, omeprazole, and ranitidine and compared it with nonexposed pregnancies between 1991 and 1996. Two different sources were used, the United Kingdom General Practice Research Database and the Italian Friuli-Venezia Giulia Health Database. The final study cohort included 1,179 pregnancies from the United Kingdom and 1,057 from Italy. Abortions or ectopic pregnancies were not included. There were 20 stillbirths and 2,261 live-born babies in both cohorts combined, with 100 offspring identified with a malformation. The overall malformation rate was 4.4%. The relative risks for nongenetic congenital malformations associated with the use of cimetidine, omeprazole, and ranitidine were 1.2 (95% confidence interval (CI): 0.6, 2.3), 0.9 (95% CI: 0.3, 2.2), and 1.4 (95% CI: 0.8, 2.4), respectively, compared with the nonexposed. No specific grouping in the distribution of malformations was observed in any of the three exposed groups. Moreover, no relation was found between drug exposure and preterm delivery or growth retardation. These findings suggest that the use of acid-suppressing drugs during the first trimester of pregnancy is not associated with a major teratogenic risk.