Previous genomewide association studies (GWAS) and meta-analyses have enumerated several genes/loci in major histocompatibility complex region, which are consistently associated with rheumatoid arthritis (RA) in different ethnic populations. Given the genetic heterogeneity of the disease, it is necessary to replicate these susceptibility loci in other populations. In this case, weinvestigate the analysis of two SNPs, rs13192471 and rs6457617, from the human leukocyte antigen (HLA) region with the risk of RA in Tunisian population. These SNPs were previously identified to have a strong RA association signal in several GWAS studies. A case–control sample composed of 142 RA patients and 123 healthy controls was analysed. Genotyping of rs13192471 and rs6457617was carried out using real-time PCR methods by Taq Man allelic discrimination assay. A trend of significant association was found in rs6457617 TT genotype with susceptibility to RA (P = 0.04, p p_c = 0.08, OR = 1.73). Moreover, using multivariable analysis, the combination of rs6457617*TT–HLA-DRB1*04 ⁺ increased risk of RA (OR = 2.38), which suggest a gene–gene interaction event between rs6457617 located within the HLA-DQB1 and HLA-DRB1. Additionally, haplotypic analysis highlighted a significant association of rs6457617*T–HLA-DRB1*04 ⁺ haplotype with susceptibility to RA (P = 0.018, p_c = 0.036, OR = 1.72). An evidence of association was shown subsequently in antiCCP ⁺ subgroup with rs6457617 both in T allele and TT genotype (P = 0.01, p_c = 0.03, OR = 1.66 and P = 0.008, p_c = 0.024, OR = 1.28, respectively). However, no association was shown for rs13192471 polymorphism with susceptibility and severity to RA. This study suggests the involvement of rs6457617 locus as risk variant for susceptibility/severity to RA in Tunisian population. Secondly, it highlights the gene–gene interaction between HLA-DQB1 and HLA-DRB1.