OBJECTIVES: To assess the cost-effectiveness of edoxaban versus acenocoumarol (VKA treatment) in the prevention of stroke and systemic embolic events in patients with non-valvular atrial fibrillation (NVAF) in Spain. METHODS: A Markov model was developed and adapted to the Spanish setting to simulate the evolution of NVAF patients throughout their lifetime. The Cycle length was 1 month and different health states such as stroke, bleeding and other cardiovascular complications were defined to mimic NVAF natural history. Drug’s safety and efficacy outcomes were obtained from the Phase III trial. The analysis was conducted from the Spanish National Health System (NHS) perspective. Edoxaban and acenocoumarol costs were calculated according to recommended doses. The costs of NVAF complications and disease management costs were obtained from available Spanish published sources. An annual discount of 3% for costs and health outcomes was applied. RESULTS: Edoxaban resulted on average with 0.337 quality-adjusted life-years (QALYs) gained and 0.285 life years gained (LYG) compared with acenocoumarol. Due to the projected longer survival of patients, edoxaban could generate more costs per patient than acenocoumarol from the NHS perspective, but the incremental cost-effectiveness ratio (ICER) for edoxaban was highly cost effective, at 7,888€ per LYG and 6,671 € per QALY gained. To evaluate study robustness subgroup analyses (such CHADS2>3 score and percentage of well controlled patients), and probabilistic sensitivity analyses were performed. Those analyses confirmed the ICERs for edoxaban to be cost-effective when applying the commonly accepted cost effectiveness threshold in Spain.  CONCLUSIONS: Edoxaban is cost-effective compared with acenocoumarol from the NHS perspective in the prevention of stroke and systemic embolic events in patients with NVAF in Spain.