Aims Peripheral artery disease affects 1.2% of the population globally and is associated with an increased risk of atherothrombotic cardiovascular events, major adverse limb events and mortality. The Cardiovascular Outcomes for People Using Anti-coagulation Strategies (COMPASS) trial demonstrated positive results of rivaroxaban plus aspirin therapy compared to aspirin therapy alone in those with peripheral artery disease or carotid artery disease. We sought to estimate the cost-effectiveness from the Australian healthcare system perspective. Methods and results A Markov model was developed to simulate the experiences of a hypothetical population of 1000 individuals with peripheral artery disease or carotid artery disease, profiled on the COMPASS trial, treated with rivaroxaban plus aspirin therapy versus aspirin therapy alone. With each annual cycle, individuals were at risk of having non-fatal cardiovascular disease events, major adverse limb events, or dying. Individuals were also at risk of non-fatal major bleeding. The model had a lifetime time horizon. Costs and utilities were sourced from the literature and discounted at 5.0% annually. Rivaroxaban plus aspirin therapy prevented 143 non-fatal cardiovascular disease events, 118 major adverse limb events and 10 deaths compared to aspirin therapy alone. Conversely, 156 additional major non-fatal bleeds were accrued. With an additional 256 quality-adjusted life years gained, at an additional cost of AUD$6,858,103, the incremental cost-effectiveness ratio was AUD$26,769 (discounted) per quality-adjusted life year gained, which is below Australia’s arbitrary willingness to pay threshold of AUD$50,000. Conclusion In those with peripheral artery disease or carotid artery disease, rivaroxaban plus aspirin therapy is effective and cost-effective in the prevention of recurrent cardiovascular disease compared to aspirin therapy alone.