OBJECTIVES: To undertake an economic evaluation of rivaroxaban relative to the local standard of care, acenocoumarol, for stroke prevention in atrial fibrillation (AF) patients with one or more risk factors. METHODS: A Markov model designed to reflect the natural progression of AF patients through different health states was developed and adapted to the Greek setting. The analysis was undertaken from a payer perspective. Baseline event rates (adjusted to three month cycles) and relative treatment effects (RRs) were derived from the safety on treatment analysis of the ROCKET AF study. Utility values for events were based on literature. A treatment-related disutility of 0.05 was applied to acenocoumarol arm. Costs assigned to each health state reflect local drug acquisition, monitoring, event management and transportation costs and reflect the year 2012. An incremental cost effectiveness ratio (ICER) per quality-adjusted-life year (QALY) gained was calculated. One-way sensitivity analyses were conducted to identify key model drivers. Probabilistic analysis was undertaken to deal with uncertainty. The horizon of analysis was over patient life time and both cost and outcomes were discounted at 3.5%.   RESULTS: The average total cost of rivaroxaban-treated patients was €985 higher compared to acenocoumarol. Rivaroxaban was associated with additional drug acquisition costs (€5,275), however these were mainly offset by reduced monitoring (€3,947) and event costs (€343). Moreover, rivaroxaban was associated with a 0.22 increment in QALYs leading to an ICER of €4,517/QALY gained. Sensitivity analyses showed that the cost-effectiveness results are fairly robust with discontinuation rate of rivaroxaban, acenocoumarol monitoring visits, acenocoumarol-related utility decrement, RR for rivaroxaban versus acenocoumarol for stroke having the highest impact on results. Probabilistic analysis revealed a high probability of rivaroxaban being cost-effective at a threshold of €30,000 or €40,000/QALY. CONCLUSIONS: Rivaroxaban may represent a cost-effective option for the prevention of stroke in AF patients with one or more risk factors.