Purpose <p>Stroke is a leading cause of death and disability worldwide. Clopidogrel, an antiplatelet agent that is commonly used for the secondary prevention of ischemic stroke, yet the data on the efficacy and safety of generic versus brand-name clopidogrel remain limited. The aim of this retrospective cohort study was to compare the efficacy and safety of a specific generic formulation of clopidogrel (Thrombifree) with brand-name clopidogrel during the long-term monotherapy phase, initiated ≥ 91 days after hospital discharge, in the secondary prevention of ischemic stroke.</p> Methods <p>Patients with ischemic stroke prescribed either generic or brand-name clopidogrel were identified from the Taiwan National Health Insurance Research Database between 2008 and 2021. The efficacy was defined as recurrent ischemic stroke and safety as major bleeding. Possible confounding effects were reduced using 1:1 propensity score matching.</p> Results <p>A total of 5,540 matched pairs were included in the analysis. The incidence rate of recurrent ischemic stroke was 3.95 per 100 person-years in the generic group, and 3.43 per 100 person-years in the brand-name group (subdistribution hazard ratio [SHR] 1.09, 95% confidence interval [CI] 0.97–1.21). The risk of major bleeding was also similar between the two groups. No significant differences were observed in other secondary cardiovascular or bleeding endpoints.</p> Conclusion <p>This study showed that the specific generic clopidogrel formulation evaluated in this study demonstrated similar efficacy and safety profiles compared with the brand-name product in patients with ischemic stroke, with no statistically significant differences observed.</p>