This study aimed to assess the association of APO gene polymorphisms and ischemic stroke risk in a Chinese Han population. In this case-control study, we genotyped 14 single nucleotide polymorphisms (SNPs) in 3 APO genes in 488 cases and 503 controls using Sequenom Mass-ARRAY technology and evaluated their association with ischemic stroke using the χ2 and genetic model analysis. In the allelic model analysis, we determined three SNPs were significantly associated with ischemic stroke: rs693 with a p value of 0.042 (OR = 1.406; 95%CI = 1.011-1.956), rs651821 with a p value of 0.007 (OR = 0.760; 95%CI = 0.622-0.929) and rs662799 with a p value of 0.006 (OR = 0.755; 95%CI = 0.618-0.923). In the genetic model analysis, we found the minor allele "A" of rs693 was associated with an increased ischemic stroke risk in the additive model and dominant model. The minor allele "C" of rs651821 was associated with a decreased ischemic stroke risk in the additive model. The minor allele "G" of rs662799 was associated with a decreased ischemic stroke risk in the additive model. Additionally, strong linkage was found in 3 blocks constituted by rs1042034, rs676210, rs693, rs673548 in APOB; rs3791981, rs679899 in APOB; and rs651821, rs662799, rs17120035 in APOA5. Our data suggested that gene polymorphisms in the APO genes may exert influences ischemic stroke susceptibility in a Chinese Han population.