AIM: Clopidogrel and aspirin are commonly used drugs for the secondary prevention of cerebrovascular disease. Due to drug resistance, their preventive effect is often affected. This article explores the clinical value of clopidogrel and aspirin pharmacogenetic genetic testing in the secondary prevention of ischemic stroke. METHODS: 220 patients with mild ischemic stroke or TIA admitted to our hospital from 2021.7 to 2022.9 were included and randomly divided into individualized treatment group and clopidogrel conventional treatment group (control group). The patients were followed up for one year to observe stroke recurrence and hemorrhagic events. RESULTS: (1) Compared with the control group, the recurrence rate of ischemic stroke in the individualized treatment group after 1-year follow-up was slightly lower (5.82% vs. 7.92%, P>0.05), the risk of cerebral hemorrhage was similar, but the risk of other occurrences was increased (6.79% vs. 0.99%, P<0.05). (2) COX regression analysis showed that ESRS (HR 2.576, 95%CI 1.226-5.413, P=0.013) and history of hypertension (HR 5.517, 95%CI 1.624-18.737, P=0.006) were associated with recurrence of ischemic stroke, independent of antithrombotic regimen (HR 0.918, 95%CI 0.291-2.894, P=0.883). CONCLUSION: Aspirin GPIBA, PTGS1, and ITGB3 gene polymorphisms have limited significance in guiding antiplatelet medication. Selecting aspirin maintenance therapy for clopidogrel CYP2C19*2*3 allele carriers cannot significantly reduce the risk of recurrence of minor ischemic stroke and may increase other bleeding risks. COX regression analysis shows that ESRS and history of hypertension are independent risk factors for stroke recurrence.