Background: Proton pump inhibitor (PPI) lansoprazole acts as a liver X receptor agonist, which plays a crucial role in the crosstalk of osteoblasts and osteoclasts in vitro and during bone turnover in vivo. However, epidemiological studies on the association between the use of lansoprazole and osteoporosis risk are limited. We aimed to determine the risk of developing osteoporosis in patients with lansoprazole use. Methods: A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study includes 655 patients with lansoprazole use (the exposed cohort) and 2620 patients with other PPI use (the comparison cohort). The main outcome was the primary diagnosis of osteoporosis. The hazard ratios (HRs) and 95% confidence intervals (CIs) were used to assess the association between the use of lansoprazole and risk of osteoporosis. Results: Patients receiving lansoprazole treatment had a reduced risk of osteoporosis as compared with those undergoing other PPI therapy (adjusted HR, 0.56; 95% CI, 0.46–0.68). Moreover, this inverse association is evident in both sexes and in various age groups. Conclusions: This population-based cohort study demonstrated that lansoprazole use was associated with a reduced risk of osteoporosis. The clinical implications of the present study need further investigations.