Inflammation, characterized by the recruitment and adhesion of circulating leukocytes by cellular adhesion molecules, plays an important role in the pathogenesis of atherosclerosis. Genetic analyses of platelet-endothelial cell adhesion molecule-1 (PECAM-1), a key adhesion molecule in the progression of atherosclerosis, have provided conflicting results regarding the role of variation within the PECAM-1 gene and risk for coronary heart disease. No studies have examined the association of this polymorphism with ischemic stroke. Therefore, we investigated that PECAM-1 gene polymorphism and its soluble level are associated with ischemic stroke in Chinese population. We analyzed single-nucleotide polymorphisms of PECAM-1 gene Leu125Val, Asn563Ser, and Gly670Arg in 265 patients with ischemic stroke and 280 age- and sex-matched controls, using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method, while soluble PECAM-1 (sPECAM-1) levels were measured by enzyme-linked immunosorbent assay. There were significant differences in the genotype and allele frequencies of PECAM-1 gene Leu125Val polymorphism between the group of patients with ischemic stroke and the control group (p < 0.05). sPECAM-1 levels were increased in patients with ischemic stroke compared with controls (p < 0.01). Moreover, genotypes carrying the PECAM-1 125Val variant allele were associated with increased PECAM-1 levels compared to the homozygous wild-type genotype in patients with ischemic stroke. The Leu125Val polymorphism of PECAM-1 and its sPECAM-1 levels are associated with ischemic stroke in Chinese population. Our data suggest that the PECAM-1 gene may play a role in the development of ischemic stroke.