OBJECTIVES The objective of this study was to evaluate the cost-effectiveness of apixaban in the prevention of thromboembolic events in patients with non-valvular atrial fibrillation (NVAF) relatively to standard of care (warfarin or aspirin) from the Italian National Health System (SSN) perspective. METHODS A previously published Markov model was adapted for Italian NVAF patients. Clinical effectiveness data were derived from head-to-head randomized trials (ARISTOTLE and AVERROES); main events considered in the model were ischemic and hemorrhagic stroke, systemic thromboembolism, bleeds (both major and clinically relevant minor) and cardiovascular hospitalizations.  Expected survival was projected beyond trial duration using national mortality data adjusted for individual clinical risks and adjusted by utility weights for health states derived from literature. Unit costs were collected from published Italian sources. Costs (2013 €) and health gains accruing after the first year were discounted at an annual 3.5% rate. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to assess the effect of input uncertainty.    RESULTS Incremental LYs (0.31/0.19), QALYs (0.28/0.20), and costs (1,932/1,104) are predicted with the use of apixaban relative to aspirin and warfarin, respectively. The incremental cost effectiveness ratios (ICERs) of apixaban were € 6,794 and € 5,607 per QALY gained, respectively. In PSA, the probability of apixaban being cost effective relative to aspirin and warfarin was 95% and 93%, respectively, for a WTP threshold of € 20,000 per QALY gained. Univariate analyses indicate that results were most sensitive to variations of the absolute risk reduction for cardiovascular events with apixaban.  CONCLUSIONS Apixaban is expected to increase life expectancy and quality-adjusted life expectancy, but also costs dedicated to Italian NVAF patients, as compared to standard of care. The resulting ICERs have high probabilities of being below the conventional thresholds of WTP for health benefits of the SSN, indicating efficient allocation of health care resources.