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Clopidogrel is widely prescribed to individuals with acute coronary syndrome (ACS) treated using percutaneous coronary intervention (PCI). This systematic review aims to synthesize existing economic evidence of clopidogrel in patients with ACS undergoing PCI. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to systematically review the literature with relevant keywords in the databases like PubMed, Cochrane, Scopus, cost effectiveness (CE) analysis registry, Health Technology Assessment (HTA) Database, Health Economic Evaluation Database (HEED), to identify studies on economic evaluation of clopidogrel in patients with ACS undergoing PCI from 1991 to 2024. This review included only full cost-effectiveness analyses of clopidogrel compared to other antiplatelet drugs in patients with ACS undergoing PCI and excluded partial economic evaluations. Data were extracted from the shortlisted articles and summarized. Only seven studies fulfilled all inclusion criteria and were included in the qualitative synthesis. Of these, four primarily evaluated the economic impact of clopidogrel compared to Prasugrel. The overall incremental cost-effectiveness ratios (ICERs) ranged between $−272,230/quality-adjusted life year (QALY) to $60,628/QALY. The wide variation in ICERs is explained by using different study designs, countries, cost assumptions, economic modelling approaches, and comparators and WTP thresholds, which may restrict the applicability of these findings in a broader population. Cost-effectiveness of clopidogrel in ACS patients undergoing PCI is highly related to the comparator used in the analysis. Additional comprehensive evaluations using alternative comparators are necessary to ascertain the cost-effectiveness of clopidogrel. • This systematic review synthesizes the existing research evidence of clopidogrel in individuals with ACS treated with PCI. • Seven full cost-effectiveness studies comparing clopidogrel with other antiplatelet drugs were included in the review. • ICER values varied widely from dominant to high cost per QALY across different healthcare settings. • Cost-effectiveness depended strongly on the comparator choice, model used, and the country’s willingness-to-pay threshold.