Objective To evaluate the association of the ANRIL and PON gene with cognitive impairment in acute ischemic stroke (PSCI) using single nucleotide polymorphisms (SNPs) as gene marker and any possible interactions between specific genotypes and traditional risk factors for PSCI among a Han Chinese cohort. Methods The samples consisted of the Han people with first-ever ischemic stroke (IS) at the age of ranging from 17 to 70 years. The cognitive function was evaluated at 2 weeks after IS onset according to the Chinese version of Mini-Mental State Examination (MMSE). The SNPs were detected by SNPscan methods based on polymerase chain reaction principle. Allelic and genotypic frequency differences were evaluated using a Logistic regression model. The interactional analyses were performed using the multifactor dimensionality reduction test. Results A total of 255 patients were entered into the study and 88 patients were diagnosed as PSCI (34.5%). We found an association between the rs10116277 G allele (OR=0.128,P=0.001), rs1333049 C allele (OR=1.472,P=0.038), rs12026 (OR=2.595,P=0.015)and rs7493 GG genotype (OR=2.597,P=0.015), and rs3735590 A allele (OR=1.731,P=0.034) and PSCI. In addition, we also found interactions for PSCI risk between SNPs in the ANRIL and PON gene and traditional risk factors, including: rs10116277 TT genotype, rs1333049 CC genotype and high levels of hsCRP (OR=5.049, P=0.005); rs10116277 TT genotype, rs1333049 CC genotype and infarction volume (OR=8.322, P=0.001); rs10116277 TT genotype and carotid stenosis (OR=4.067, P=0.001); as well as rs3735590 GG genotype and infarction volume (OR=5.176, P<0.001). Conclusion The ANRIL and PON SNPs as well as the gene-environment interactions play an important role in PSCI in a Han Chinese cohort.