OBJECTIVES The study assessed the lifetime cost-effectiveness of apixaban in preventing thromboembolic events in non-valvular atrial fibrillation (NVAF) patients, as compared to other novel oral anticoagulant agents (NOACs), from the Italian Health System (SSN) perspective. METHODS A previously published Markov model was adapted. Baseline clinical risks were assigned based on the demographic and clinical features of the patients; effectiveness parameters derived from adjusted indirect comparison using warfarin as link. Expected survival was projected beyond trial duration using national mortality data adjusted for clinical risks and weighted by published utilities. Unit costs were collected from official and published Italian sources. Costs (2013-€) and health gains occurring after the first year were discounted at an  annual 3.5% rate.  Deterministic and probabilistic sensitivity analyses (DSA&PSA) were carried out. RESULTS In the short to  medium term, apixaban was associated with marginal LYs and QALYs gains and slight savings. However, as apixaban extended expected survival versus dabigatran (110mg), dabigatran (150mg) and rivaroxaban (0.13, 0.08, and 0.06 LYs or 0.11, 0.07, and 0.05 QALYs), expected total lifetime costs exceeded those of these comparators (319, 282, 16 €). Corresponding ICERs were estimated in €2,911, €3,882 and €327 per QALY gained. In PSA, the probabilities of apixaban being cost effective with a WTP threshold of 20,000 €/QALY gained were 99%, 92% and 93% for the same comparisons. The most influential parameter according to DSA was daily cost of NOACs, but the corresponding ICERs remained well below commonly accepted WTP values. CONCLUSIONS Apixaban is expected to be more effective than dabigatran and rivaroxaban in Italian NVAF patients, and marginally more costly due to costs in added years of life. The ICERs have a high likelihood of being below conventional thresholds of WTP for health benefits of the SSN and suggest that apixaban is cost-effective compared with other NOACs.