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Objectives: The purpose of this study was to investigate the association between fracture risk and proton pump inhibitor (PPI) use to establish evidence for defining high-risk groups of fracture among PPI users. Methods: A case-control study was performed using the National Health Insurance Sample Cohort Database from January 2002 to December 2013. The cases included all incidences of major fractures identified from January 2011 to December 2013, and up to four controls were matched to each case by age, gender, osteoporosis, and Charlson comorbidity index. Conditional logistic regression was used to calculate the adjusted odds ratio (aOR) and associated 95% confidence interval (CI). Results: Overall, 14,295 cases were identified, and 63,435 controls were matched to the cases. The aOR of fractures related to the use of PPIs was 1.06 (95% CI: 1.01-1.11). There was a statistically significant association between fracture and PPI use within 3 months of the last dose, and a trend of increasing fracture risk with increasing cumulative PPI dose. The risk of fracture was significantly higher in patients who took PPIs for more than 1 year during the 2-year observation period. Conclusion: Patients who have been using PPIs for more than 1 year should be warned about the risk of fracture during or at least 3 months after discontinuing the PPI.