Lansoprazole is a proton pump inhibitor (PPI), frequently used for the treatment of gastroesophageal reflux disease. It may also be used in pregnant women; however, the safety of lansoprazole exposure during pregnancy remains unclear. In this study, we assessed the risk of major malformation and the effects on other pregnancy and birth outcomes resulting from lansoprazole exposure during the first trimester based on data from two Japanese facilities that provided counseling on drug use during pregnancy between 1988 and 2017. The study included 106 cases of lansoprazole exposure and 1788 control individuals. The risk of major malformation following exposure to lansoprazole after the first trimester was compared with that of the control group administered non-teratogenic drugs during the first trimester. The incidence of major malformation in singleton liveborn infants was 1.0% (1/96) in the lansoprazole group and 1.9% (31/1670) in the control group. Adjusted multivariable logistic regression analysis revealed no significant difference in the incidence between the control and lansoprazole groups [adjusted OR: 0.51 (95% confidence interval: 0.07–3.79), p=0.507]. Furthermore, no differences were observed between the two groups in the incidence of stillbirth, miscarriage, and birth weight. The results indicate that lansoprazole exposure during the first trimester is not associated with an increased risk of major malformations. Overall, our findings provide valuable insight for selecting gastroesophageal reflux disease medications for use in pregnant women.