OBJECTIVES: The purpose of this study was to investigate the risk of getting atrial fibrillation in a year after receiving the first medication and analyze cost-effectiveness in avoiding the adverse event among alendronate, raloxifene, and hormone replacement therapy.  METHODS: We used the 2000-2008 National Health Insurance Research Database (NHIRD) to identify 10,353 patients who had the first medication with drugs and classify them into three groups (7439 patients defined as those who used alendronate and 2077 patients with raloxifene as well as 837 patients with hormone replacement therapy). Cox proportional hazard model was used to estimate the hazards of getting atrial fibrillation among three drugs. Also, this study used the cost-effectiveness analysis to estimate the incremental cost effective ratio in avoiding the adverse event as they were treated by different treatments.  RESULTS: The Cox regression analyses demonstrated that alendronate group (HR=1.52, 95%CI: 0.55 - 4.19) and raloxifene group (HR=1.38, 95%CI: 0.46 - 4.21) had higher risk in getting atrial fibrillation than hormone replacement therapy group, but there were not statistically significant. As to the cost-effectiveness analysis in avoiding 1% chance of the adverse event, the average medication expenditure of hormone replacement therapy group would increase 2,916.7 USD (ICER=2,916.7, 95%CI: 1063.3 – 5,102.9) and 2,266.7 USD (ICER=2,266.7, 95%CI: -411.5 – 5,068.1), comparing to alendronate group and raloxifene group respectively.  CONCLUSIONS: People with osteoporosis that were treated by bisphosphonate or raloxifene are better in terms of overall economic cost than those who used hormone replacement therapy.