Peroxisome proliferator-activated receptor (PPAR)-gamma2 has important effects to insulin sensitivity, atherosclerosis, inflammation and endothelial cell function. Through these effects, PPAR-gamma2 might be involved with the ischemic stroke in type 2 diabetes. To determine the role of PPAR-gamma2 in genetic susceptibility to ischemic stroke in type 2 diabetes, we genotyped 302 ischemic stroke patients, 283 healthy controls and 141 type 2 diabetic patients without ischemic stroke (diabetes duration >10 years) for PPAR-gamma2 Pro12Ala polymorphism by polymerase chain reaction-restriction fragment length polymorphism methods. PPAR-gamma2 Pro/Ala genotype were lower in ischemic stroke patients than those observed in the control group (4.0% vs. 9.9%, OR=0.38, P=0.0046), and it were associated with the incidence of ischemic stroke in the multivariate analysis (OR=0.43, P=0.025). Genotypic analysis revealed that ischemic stroke patients with type 2 diabetes displayed a great lower prevalence of the Pro/Ala genotype (2.3%) than controls (9.9%) (OR=0.21, P=0.0047). And Pro/Ala genotype of type 2 diabetes patients with ischemic stroke were lower than type 2 diabetes patients without ischemic stroke (2.3% vs. 8.5%, OR=0.25, P=0.0321), however the significant association with ischemic stroke was not detected in the multivariate analysis (OR=0.27, P=0.051). These results suggest that the Pro/Ala genotype of PPAR-gamma2 Pro12Ala polymorphism may be associated with reduced risk for ischemic stroke, and the possibility that it might have a protective effect for ischemic stroke with type 2 diabetes.