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.