Rheumatoid arthritis (RA), the most common autoimmune inflammatory disease of the joints, is a multifactorial disease, involving both genetic and environmental risk factors. TNFAIP3 (tumor necrosis factor, alpha-induced protein 3) gene located in a region of genetic susceptibility in RA is an attractive candidate to be involved in autoimmunity disorders. Our aim was to test the single nucleotide polymorphism rs6920220 located near TNFAIP3 in a case-control study in Tunisian population. The rare allele rs6920220-A was reported to have a risk effect on RA in several genome-wide association studies. Our results revealed a trend of an association of rs6920220-A allele with RA and genotypes containing this allele were in a higher proportion in RA patients than in matched controls. These findings have to be confirmed by a replication in largest RA and control groups of the same ethnic origin. TNFAIP3 gene may have a key role in autoimmunity through its action as a negative regulator of the NF-κB pathway. Further functional investigations are required to understand the mechanism by which this gene is involved in the RA pathogenesis.