Objectives: Stroke prevention is the main goal in treating patients with atrial fibrillation (AF). Treatment with anticoagulants, such as vitamin-K antagonists (VKAs; e.g. warfarin and cumarines), was demonstrated to be an effective strategy. However, even though VKAs are the current standard therapy recommended by different guidelines, the significant risk of bleeding and the requirement for a regular monitoring are limiting its use. Apixaban is a novel oral anticoagulant (NOAC) associated with significantly lower hazard rates for stroke/systemic embolism major hemorrhage and discontinuations, compared to VKAs. This study evaluated the cost-effectiveness (CE) of apixaban compared to VKAs in the base-case analysis and alternatively to other NOACs for stroke prevention in non-valvular AF patients in The Netherlands. Methods: A global Markov model developed by United BioSource Corporation was modified to reflect the use of oral anticoagulants in The Netherlands. The model used efficacy data from a published indirect treatment comparison of NOACs and cost data from Dutch costing studies as inputs. Following health states were included in the model: non-valvular AF, primary and recurrent ischemic and hemorrhagic stroke, systemic embolism, myocardial infarction intracranial hemorrhage, other major and non-major bleedings, treatment discontinuations and death. Main outcomes were quality adjusted life years (QALY) and costs. Univariate and probabilistic sensitivity analyses (PSA) were conducted on the incremental cost-effectiveness ratio (ICER). Results: In the base-case analysis apixaban treatment compared to VKAs has an ICER well below an informal minimal willingness-to-pay threshold of € 20,000/QALY for The Netherlands (i.e. around € 7,000/QALY). PSA showed that the results of the base-case analysis were quite robust. Potentials exist for apixaban to be dominant over the other NOACs, rivaroxaban and dabigatran depending on hazard ratios, risks for complications and local price levels. patients in The Netherlands. Conclusions: In patients with AF, we found apixaban to be a cost-effective option in The Netherlands, compared to VKAs.