Abstract Ischemic stroke (IS) is a heterogeneous multifactorial disorder caused by both genetic and environmental factors. A genome-wide association study on stroke in Caucasians identified a variant on chromosome 4q25 that is significantly associated with IS, with the strongest risk for cardioembolic stroke (CES). The current study aims to investigate the association of the rs1906591 variant on 4q25 with IS through a case-control study in a Chinese Han population. A total of 712 IS patients and 774 control subjects were involved in the current research. Stroke subtyping was performed according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The genotypes were determined using the SNaPshot technique. The association of the genotypes with the risk of IS was estimated using logistic regression analysis. The rs1906591 single nucleotide polymorphism variant was associated with the CES subtype in both recessive and additive models (recessive model: odds ratio [OR]=2.58, 95% confidence interval [CI] 1.47–4.53, p=0.001, adjusted OR=2.71, 95% CI 1.48–4.96, p=0.001; additive model: OR=2.50, 95% CI 1.19–5.25, p=0.015, adjusted OR=2.83, 95% CI 1.24–6.50, p=0.013). This result indicates that patients with the AA genotype have a higher rate of CES than other genotypes. However, the rs1906591 variant was not significantly associated with the overall incidence of stroke or other stroke subtypes. The rs1906591 variant is significantly associated with CES in the Chinese Han population, but not with other stroke subtypes.