OBJECTIVES: To determine if clopidogrel plus aspirin is cost-effective compared to aspirin alone for patients following ACS, from the Australian health care perspective. METHODS: A Markov model was constructed by extrapolation of data from the Australian Acute Coronary Syndromes Prospective Audit (ACACIA) registry (n=2553) in the first model cycle, and the Reduction in Atherothrombosis for Continued Health (REACH) registry (n=2567 Australian patients) in subsequent cycles. Decision analysis was applied to compare clopidogrel plus aspirin against aspirin alone. Efficacy data were drawn from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. A utility study was conducted in 2007 with 86 participants using health states validated by clinical experts. Drug and disease costs were obtained from literature and health care reimbursement fees, and updated using Australian health price indices. An annual discount rate of 5% was applied to all costs and effects beyond one year in accordance with reimbursement guidelines. Twenty sensitivity analyses were undertaken, varying the 95% confidence intervals surrounding efficacy measures from CURE, uncertainty in cost and utility inputs and variations to time horizons and discount rates. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) with a ten-year time horizon was A$14,496/QALY and remained below the unofficial cost-effective threshold of $A40,000/QALY throughout all sensitivity analyses. Treatment remained cost-effective up to an inflated clopidogrel cost of 229%, and even when acute hospitalization costs were removed (A$20,267/QALY). The five-year ICER was A$20,124/QALY. Sensitivity analyses demonstrated that the ICER ranged from A$6443/QALY when the risk of events observed in ACACIA were applied to all years, up to A$36,974/QALY using the 95% upper confidence interval for efficacy. CONCLUSIONS: Clopidogrel with aspirin represents a highly cost-effective treatment option for patients with ACS in Australia. This was confirmed by the Australian reimbursement authority’s recent recommendation that treatment with clopidogrel plus aspirin be reimbursed for ACS patients.