OBJECTIVES: The gene of CYP2C19 is highly polymorphic and influences the metabolism of clopidogrel. Using CYP2C19 genotype data, patients at risk of inadequate antiplatelet effect with clopidogrel could be identified and treated with a new antiplatelet agent (prasugrel or ticagrelor). This study aimed to evaluate the cost-effectiveness of genotype-guided therapy versus universal clopidogrel treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).   METHODS: A lifelong Markov model, from the perspective of healthcare provider, was designed to simulate two treatment strategies: universal generic clopidogrel and genotype-guided therapy (generic clopidogrel for patients without CYP2C19 loss-of-function (LOF) allele and new oral antiplatelet drug (prasugrel or ticagrelor) for patients with at least one LOF allele). Model inputs were derived from published meta-analysis and clinical trials. Direct medical costs and quality-adjusted life-year (QALY) gained were the primary model outcomes. One-way and probabilistic sensitivity analyses were performed. RESULTS: Base-case analyses illustrated that universal clopidogrel strategy cost $76,335 with 7.919 QALYs, while genotype-guided therapy cost $73,131 with 8.068 QALYs. With a threshold of willingness-to-pay of $50,000 per QALY, genotype-guided therapy remained the preferred strategy throughout variations of all model inputs in one-way sensitivity analysis with no threshold value identified. The most influential factor was the probability of ischemic heart disease (IHD) state turned to death, followed by the possibility of post myocardial infarction state turned to death, cost of PCI and utility of IHD. In probabilistic sensitivity analysis, genotype-guided therapy was dominant with cost-saving $3472 (95% confidence interval (CI): 3448-3496) and a gain of 0.2425 QALY (95% CI: 0.2421-0.2429) compared with universal generic clopidogrel. CONCLUSIONS: Genotype-guided therapy appears to be the preferred strategy when comparing to universal generic clopidogrel treatment for patients with ACS undergoing PCI.