Immunoglobulin A nephropathy (IgAN), the most common form of primary glomerular diseases worldwide, is a complex multifactorial disease. Previous genome wide association studies (GWAS) reported that variants CARD9 and VAV3 genes were associated with immunoregulation and susceptibility to IgAN. In this study, we further validated the associations and explored the interaction effect of rs4077515 and rs17019602 in IgAN patients.There was no significant correlation between the two variants and IgAN (P > 0.05). The gene-gene analysis showed that rs4077515 and rs17019602 had interaction effect on the susceptibility to IgAN. For additive interaction, the CT or TT of rs4077515 and GG of 17019602 genotype combination conferred a 2.56-fold risk of IgAN reference to CC of 4077515 and AA of 17019602 (OR = 2.56, 95% CI: 0.98-6.69, P = 0.049). In our study, clinical data was available for 543 patients. In comparison, neither rs4077515 nor rs17019602 showed significant association between genotype distribution and clinical parameters in IgAN patients (P > 0.05).The case-control study included 586 patients with IgAN and 606 healthy controls. Variant rs4077515 of CARD9 gene and rs17019602 of VAV3 gene were genotyped by the ABI TaqMan probe assay.The interaction effect of the variants of CARD9 and VAV3 genes increases the susceptibility to IgAN.