OBJECTIVE: Clopidogrel is an antiplatelet agent that has been shown to reduce the risk of ischemic stroke (IS), myocardial infarction (MI), and vascular death ("atherothrombotic events") compared with aspirin in patients with recent IS, recent MI, or symptomatic peripheral arterial disease (PAD). The objective of this study was to estimate the cost-effectiveness of clopidogrel versus aspirin in these patients. METHODS: We developed a Markov model in which patients with recent IS, recent MI, or PAD were assumed to receive lifelong therapy with clopidogrel or aspirin. Reduction in risk of atherothrombotic events for clopidogrel (vs aspirin) was estimated using data from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) clinical trial. Costs considered in the model included those of antiplatelet therapy, inpatient and outpatient treatment of ischemic stroke, MI, and bleeds, and long-term care for patients with disability. We examined the cost-effectiveness of clopidogrel for subgroups of patients defined on the basis of age at therapy initiation (55, 65, and 75 years) and gender. Cost-effectiveness was assessed using the ratio of the difference (clopidogrel minus aspirin) in expected lifetime medical-care costs to the corresponding difference in life expectancy. A 3% discount rate was used. RESULTS: One hundred patients with recent IS, recent MI, or PAD receiving clopidogrel would experience 4.5-6.3 fewer atherothrombotic events and 3.6-8.7 fewer bleeds over their lifetimes in comparison with 100 patients receiving aspirin. The expected gain in life-years ranges from 0.33-0.69 per patient. Expected total lifetime medical-care costs are $9,222-$16,850 higher for clopidogrel patients. Cost-effectiveness of clopidogrel ranges from $40,204-$49,107 per life-year saved, and is sensitive to the assumed risk reduction for clopidogrel. CONCLUSION: Clopidogrel is cost-effective versus aspirin in patients with recent IS, recent MI, or PAD.