This study explored whether inflammatory gene including C-reactive protein (CRP) and growth arrest-specific gene 6 (GAS6) are related to the etiology of ischemic stroke (IS), and to verify their potential interaction upon susceptibility to IS in Chinese population. A total of 236 patients with IS and 291 non-IS subjects were enrolled. Five single nucleotide polymorphisms (SNPs) in two candidate genes (CRP and GAS6) for IS were examined and determined by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and detected by DNA sequencing. We evaluated the association between SNPs and the risk of IS and evaluated their potential gene-gene interactions by using the generalized multifactor dimensionality reduction (GMDR), interaction dendrogram, entropy analysis and Interaction circle graph. A significant gene-gene interaction was then selected. We further tested the best model by logistic regression models. The results showed no significant difference between the IS (or its subtypes) group and the control group in the single-locus of all the analyzed variants. GMDR analysis indicated that the CRP SNPs rs3093059 and the GAS6 SNPs rs7400722 shared strong synergism in LAA analysis (Testing accuracy = 59.66%, CVC = 10,p = 0.0107). Dendrogram and circle graph analysis indicated a more-than-additive effect between the two loci. Furthermore, a recessive model of the two-locus interactions was confirmed by multivariate logistic regression model (OR = 1.940, 95% CI: 1.068-3.525,p = 0.030). The results indicate that CRP and GAS6 genes may fully participate in affecting the susceptibility to IS by gene-gene interaction, and may be conducive to provide a novel area for IS research.