Objective: To determine the clinical and cost effectiveness of apixaban compared to aspirin in the prevention of thromboembolic events for patients with atrial fibrillation for whom vitamin K antagonist (VKA) therapy (warfarin) has been considered unsuitable. Methods: A previously published Markov model with yearly cycles was updated. Information from the Apixaban Versus Acetylsalicylic acid to prevent Stroke in Atrial Fibrillation (AVERROES) trial in combination with other population data was used to simulate the costs and effects of apixaban compared to aspirin over 10 years. The model comprised five health states. Costs from an Australian healthcare perspective were estimated from published sources for the year 2015. The main outcome of interest was number needed to treat (NNT), number needed to harm (NNH), the incremental cost-effectiveness ratio (ICER) [cost per quality-adjusted life-year (QALY) gained, and cost per year of life saved (YoLS)]. Costs and benefits were discounted at 5.0 % per annum. Results: For each patient followed up over 10 years, NNT to prevent one additional event (thromboembolic event, death) for apixaban compared to aspirin was 4.6 and 11.8, respectively. NNH was 35.9 for non-fatal major bleeding. The model predicted that compared to aspirin, apixaban would lead to 0.33 YoLS (discounted) and 0.29 QALYs gained (discounted), at an incremental cost of AUD$1996 (discounted). This resulted in ICERs of AUD$6011 per YoLS and AUD$6929 per QALY gained. In the sensitivity analyses, ICERs were most sensitive to efficacy measures derived from the AVERROES study, and time frame. Conclusion: Compared to aspirin, apixaban is likely to be cost effective in preventing thromboembolic disease among VKA unsuitable patients with atrial fibrillation.