OBJECTIVES: To assess the cost-effectiveness of apixaban versus rivaroxaban in the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF) in Spain. METHODS: A Markov model was developed to simulate the evolution of NVAF patients throughout their lifetime. Cycle´s length was 6 weeks and 10 health states such as stroke, bleeding and other cardiovascular complications were defined. Drug´s safety and efficacy outcomes were obtained from a meta-analysis of pairwise indirect comparisons. The analysis was made from the Spanish National Health System (NHS) and the societal perspective. Apixaban and rivaroxaban pharmacological costs were calculated according to their recommended doses (5 mg twice daily (BID) and 20 mg once-a-day (QD), respectively). The cost of NVAF complications and disease management were obtained from Spanish sources. An annual discount rate of 3.5% for costs and health outcomes was applied. RESULTS: Model results illustrate that 1,000 patients with NVAF treated with apixaban during their lifetime could avoid numerous complications versus rivaroxaban (9 strokes, 10 intracranial bleedings, 1 systemic embolism, 32 major bleedings, 52 clinically relevant non major bleedings and 12 related deaths). The use of apixaban was associated with 0.062 life years (LYG) and 0.049 quality-adjusted life-years (QALYs) gained when compared to rivaroxaban. Due to the lower expected mortality of patients, apixaban generated more costs per patient vs. rivaroxaban from the NHS perspective (115 €), but savings would arise from the societal perspective (-241 €). Incremental cost-effectiveness ratio results were 1,855 € per LYG and 2,347 € per QALY gained for the NHS analysis. Apixaban was dominant (more effective and less costly than rivaroxaban) from the societal perspective. Deterministic and probabilistic sensitivity analyses confirmed these results. CONCLUSIONS: According to this analysis, apixaban is a cost-effective treatment compared with rivaroxaban for the prevention of stroke in patients with NVAF in Spain.