OBJECTIVES: To conduct an economic analysis comparing treatment with clopidogrel against aspirin in patients with peripheral artery disease, a recent stroke, or a recent myocardial infarction from the Greek third-party-payer perspective.  METHODS: A Markov model with a 6-month cycle length was developed to evaluate the lifetime cost-effectiveness of clopidogrel versus aspirin. The effect of clopidogrel was applied only during the first 2 years of the model and this was retrieved from CAPRIE trial. Local utility data were used to estimate quality-adjusted life years (QALY). The state-specific costs consists of the costs that reflect and encapsulate all resource used for the care of patients within the health care system during a 6-month period in the acute and follow-up phase, separately. The cost-effectiveness of clopidogrel over aspirin was evaluated by calculating the incremental cost per life year saved (LYS) and incremental cost per QALY saved (ICER). A probabilistic sensitivity analysis was conducted and the results are presented as mean (95% Uncertainty Interval (UI)).  RESULTS: The analysis showed that the discounted survival was 11.83 (11.41-12.22) years and 12.17 (11.75-12.55) years in aspirin and clopidogrel treatment group, respectively, a difference of 0.27 (0.10-0.45) life-years. The corresponding discounted QALYs were 8.63 (8.34 – 8.91) and 8.84 (8.54–9.10), respectively.  The cumulative lifetime costs per patient were €19,880 (€18,863–€20,939) and €21,039 (€20,006–€22,089), for aspirin and clopidogrel treatment arm, respectively. The ICER was calculated to be € 4,921 (€ 3,079–€ 9,969) for each LYS and €6,326 (€ 3,737–€ 16,699) for each QALY saved. For a “willigness-to-pay” threshold of € 9,500 per discounted QALY, clopidogrel was found to be cost-effective in more than 90% of randomly sampled analyses.  CONCLUSIONS: This economic analysis indicates that treatment with clopidogrel for secondary prevention of cardiovascular events in atherothrombotic patients is a cost-effective antiplatelet treatment over aspirin in a Greek third-party payer perspective.