Ischemic stroke (IS) is a global cerebrovascular disease with high morbidity and mortality. CYP2C9 genetic variants are significantly involved in the development of many diseases. However, the impacts that CYP2C9 genetic variants on the risk of IS remain to be comprehensively understood. We aim to determine the association of CYP2C9 with IS susceptibility in the Chinese Han population. This study recruited a total of 643 patients with IS and 643 healthy controls. CYP2C9 single-nucleotide polymorphisms (SNPs) were tested by the MassARRAY iPLEX platform. The associations of CYP2C9 polymorphisms (rs10509679, rs1934967, rs1934968, and rs9332220) and IS risk were analysed by the logistic regression analysis. Our study showed that rs10509679 G > A was significantly related to increased risk of IS (OR= 1.48, 95% CI= 1.05-2.09, p = 0.024). The stratified analysis further demonstrated that rs10509679 was correlated with an increased susceptibility to IS patients in subgroups of people aged> 60 years, those with BMI< 24, smokers, drinkers, and those without diabetes. False-positive report probability analysis was further carried out to verify the significant findings. In haplotype analysis, individuals carrying the Ars10509679Crs1934967Grs1934968Grs9332220 haplotype exhibit an elevated risk of IS occurrence. In summary, CYP2C9 rs10509679 G > A may be associated with the risk of IS.