Juvenile idiopathic arthritis (JIA) refers to a group of chronic childhood arthropathies of unknown etiology. In the present study, the genetic association between the variants in PTPN22, IRF5 and TYK2 genes and susceptibility to JIA was investigated. The distributions of 16 variants in PTPN22, IRF5 and TYK2 genes were analyzed by direct sequencing in 378 patients with JIA and 378 healthy controls. Odds ratios and 95% confidence intervals were used to evaluate the association between the gene variants and JIA. The gene-gene interactions were investigated using multifactor dimensionality reduction. All allelic and dominant models of PTPN22 rs1214414, rs1214418, rs1746853, rs3765598 and rs3811021 were significantly associated with JIA risk (P<0.05). IRF5 rs10954213 in both allelic and dominant models, as well as the allelic model of rs2004640, was significantly related to JIA risk (P<0.05). In addition, the allelic, recessive and dominant models of TYK2 rs280500, rs280519, rs2304256 and rs12720270 were significantly related to JIA risk (P<0.