E-selectin is an important inflammatory cytokine involved in the pathogenesis of various diseases such as atherosclerosis and stroke. We investigated the association of E-selectin gene polymorphism (S128R) with ischemic stroke and its subtypes. We studied 610 patients with ischemic stroke and 610 age- and sex-matched healthy controls. The ischemic stroke was classified according to Trial of Org10172 in Acute Stroke Treatment (TOAST). E-selectin gene polymorphism (S128R) was determined by polymerase chain reaction-restriction fragment length polymorphism technique. We found statistically significant difference in the genotypic distribution between patients and controls (for AC vs. AA, χ(2) = 49.5; p < 0.001, odds ratio = 5.47(95 % CI, 3.25-9.21). A significant difference was observed in the frequency of C and A alleles in patients and controls (for C vs. A, χ(2) = 47.4; p < 0.001, odds ratio = 5.13 (95 % CI, 3.06-8.57). Multiple logistic regression analysis revealed that the most predictive risk factor for stroke was AC genotype (adjusted odds ratio = 1.450 (95 % CI, 1.23-2.75) and p = 0.001), hypertension, smoking, and diabetes (p = 0.001 in each case). We also found a significant association of AC genotype with intracranial large artery atherosclerosis (p < 0.01, odds ratio = 9.37, (95 % CI, 5.31-16.5) and small artery occlusion (p < 0.0001, odds ratio = 9.81 (95 % CI, 4.94-19.4). Our results indicate that the individuals bearing AC genotype of E-selectin gene polymorphism (S128R) are more prone to stroke than AA genotype.