Background: Osteoporosis is a progressive skeletal disease associated with an increased risk of bone fracture. This study aimed to estimate the cost-effectiveness of denosumab for osteoporotic fracture prevention compared to bisphosphonates (alendronate, ibandronate, risedronate, and zoledronate) and selective estrogen receptor modulators (raloxifene) in a cohort of postmenopausal women with osteoporosis. Methods: A Markov model was used to evaluate the cost and effectiveness of denosumab versus comparators. The model had a cycle length of 6 months and was run from the age of 68 years to individual patients' lifetime or the age of 100 years. The health states considered in the model were well, hip fracture, vertebral fracture, wrist fracture, other osteoporotic fracture, post-hip fracture, post-vertebral fracture, and death. Recent local data were used as inputs for the model parameters. A discount rate of 4.5% was applied to both costs and outcomes. Results: From the perspective of the healthcare system, denosumab was cost-effective or cost-saving compared to all comparators, considering one unit of Korea's gross domestic product per capita, USA dollar (USD) 34,870. Denosumab was cost-saving compared to ibandronate (oral) and raloxifene. Compared to alendronate, denosumab was cost-effective with an incremental cost-effectiveness ratio (ICER) of USD 767.10 per quality-adjusted life year (QALY). The ICER of denosumab vs. ibandronate IV, risedronate, and zoledronate was USD 685.63, USD 1,469.71, USD 4,668.53 per QALY, respectively. Conclusions The findings of this analysis suggest that denosumab is a cost-effective therapeutic option for preventing fractures in postmenopausal women with osteoporosis in South Korea.