OBJECTIVE: To analyze the cost-effectiveness of apixaban in the prevention of stroke in adult patients with non-valvular atrial fibrillation (NVAF), compared to other direct-acting oral anticoagulants (dabigatran, rivaroxaban, edoxaban) and the vitamin K antagonist acenocoumarol, based on data on effectiveness in clinical practice in Spain obtained in the FANTASIIA study. RESEARCH DESIGN AND METHODS: A probabilistic Markov economic model (second-order Monte Carlo simulation) was performed to analyze the costs and utilities (quality-adjusted life years, QALYs) associated with the compared treatments, according to the different probabilities of stroke, major bleeding and death observed in FANTASIIA. RESULTS: The cost per QALY gained in the patient treated with apixaban versus comparators ranged from €2,919 to €7,462. The probability of apixaban being cost-effective ranges from 91.1% (vs dabigatran 150 mg), 97.8% (vs dabigatran 110 mg), and 100% (vs. rivaroxaban, edoxaban, and acenocoumarol). CONCLUSIONS: Based on the results of the FANTASIIA study, apixaban is a cost-effective treatment (below a willingness to pay of €25,000 per QALY gained) compared to dabigatran, rivaroxaban, edoxaban, and acenocoumarol in treating patients with NVAF.