Background Rivaroxaban is a selective inhibitor of coagulation factor Xa and its combination with aspirin showed better outcomes in the prevention of recurrent cardiovascular disease than aspirin alone. Objective This analysis aimed to economically compare the cost effectiveness of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) with aspirin alone in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) and related subgroups. Methods The analysis simulates the perspective of the Italian National Healthcare Service and used a state-transition decision Markov model. Clinical efficacy data and health events risks were gathered from the COMPASS trial. Health outcomes and costs (in Euros) were evaluated over a lifetime horizon and were discounted at 3.5% per annum. Direct healthcare costs entered the analysis. Results were expressed in terms of incremental cost-effectiveness ratio (ICER), defined as cost per quality-adjusted life-year (QALY) gained. One-way deterministic and probabilistic sensitivity analyses were performed. Results For the CAD or PAD population, rivaroxaban plus aspirin was more effective and costly compared with aspirin alone. Incremental costs and efficacy produced an ICER of euro16,522 per QALY gained. Analyses found similar trends for the PAD and CAD groups, with respective ICERs of euro8003 and euro18,599, while ICERs for the other groups were lower than euro13,000 per QALY. Sensitivity analyses confirmed these findings. Conclusion Compared with aspirin alone, rivaroxaban plus aspirin is cost effective in preventing recurrent cardiovascular events in all patients with CAD or PAD, from the Italian perspective. These results could help clinicians and decision makers to develop improved strategies for cardiovascular disease prevention.