OBJECTIVES: Atrial fibrillation (AFib) patients have a higher risk of ischemic stroke and anticoagulants are widely used in stroke prevention. Recently, three new oral anticoagulant drugs (NOACs) have been made available in Taiwan (Apixaban, Dabigatran, and Rivaroxaban). This study aims to calculate the cost-effectiveness of them, comparing to Warfarin, in 65-year old patients with AFib from a perspective of Taiwan national healthcare insurance (NHI). METHODS: A Markov model, Monte Carlo simulation, and sensitivity analyses were used to assess the costs and quality-adjusted life years (QALYs) of the three NOACs and Warfarin in a Taiwanese setting. All parameters populated were obtained from the literature review and NHI database. The thresholds of the willingness to pay (WTP) at 1 and 3 times GDP per capita ($22,288 and $66,864) were used to assess the cost-effectiveness. RESULTS: In a base-case analysis, Rivaroxaban produced the most QALYs at 10.32, followed by Apixaban (9.97), Dabigatran (9.26), and Warfarin (8.91). Warfarin had the fewest costs at $30,251; Rivaroxaban cost the most at $65,665, followed by Dabigatran ($52,991) and Apixaban ($48,223). The costs per QALY gained for each NOAC (Apixaban, Dabigatran, and Rivaroxaban) versus Warfarin were $16,954, $64,931, and $25,116. Dabigatran was dominated by Apixaban and the ICER (Rivaroxaban versus Apixaban) was $49,834. In a Monte Carlo probabilistic sensitivity analysis, Apixaban, Dabigatran, and Rivaroxaban were cost-effective in 36.8%, 13.4%, 36.2% of $22,288, and 31.3%, 15.2%, 48.1% of $66,864. CONCLUSIONS: From a Taiwan NHI perspective, if affordable, and the WTP threshold is at least 1 x GDP per capita ($22,288) per QALY gained, Apixaban would be preferred to Warfarin. However, if decision-makers are willing to pay up to 2.25 x GDP per capita ($50,000) per QALY gained, then Rivaroxaban would be the optimal replacement for Warfarin in the Taiwanese setting.