Over the years, a number of published studies showed that E-Selectin gene rs5361 (S128R, Ser128Arg, A561C) variants were associated with the risk of ischemic stroke (IS). However, the results of those case-control studies were still equivocal. Therefore, we performed this meta-analysis to clarify the relationship between E-Selectin gene rs5361 polymorphism and IS risk. We searched the Web of Science, PubMed, VIP, CNKI (China National Knowledge Infrastructure) and Wanfang databases for obtainning the eligible studies according to the inclusion and exclusion criteria. Odds ratios (ORs) with its 95% confidence intervals (CIs) were calculated to evaluate the relationship of E-Selectin gene rs5361 polymorphism with IS susceptibility under the dominant and allelic model with fixed or random effects model. Totally, 13 studies with 2888 cases and 2976 controls were selected in this systematic review and meta-analysis This meta-analysis obtained that E-Selectin gene rs5361variants contributed to increase the risk of IS (C vs. A: OR = 2.23, 95%CI = 1.70-2.92, p < 0.001). We also performed a sub-analysis by ethnicity, the results indicated that rs5361 variants were related to an increased risk of IS (East Asian population: C vs. A: OR = 1.97, 95%CI =1.58-2.45, p < 0.001; African population: C vs. A: OR = 5.52, 95%CI = 3.48-8.76, p < 0.001; Caucasian population: C vs. A: OR =1.67, 95%CI =1.32-2.10, p < 0.001). Therefore, our meta-analysis suggested that C allele, AA and AC genotypes of E-Selectin gene rs5361 variants were related to an increased risk of IS in overall populations.