Background:Tumor necrosis factor (TNF)-α and -β are cytokines with a wide range of inflammatory, apoptotic and immunomodulatory activities. TNF-α promoter −308 G < A polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results.Objective:The aim of this study is to elucidate a possible association of TNF-α (G–308A) and TNF-β (A+252G) polymorphisms with the susceptibility of RA in Saudi patients.Patients and methods:This case control study consisted of 232 Saudi subjects including 106 RA patients and 126 matched controls. Genomic DNA was extracted using QIAampR DNA mini kit (Qiagen CA, USA). TNF-α and TNF-β genes were amplified using Arms primers.Results:The frequencies of TNF-α (−308) allele G and genotype GG were significantly higher in RA patients as compared to controls while allele A and genotype AA were predominant in control group. On the other hand the frequency of TNF-β (+252) GG and AA genotypes were significantly higher in RA patients as compared to controls while GA genotype was predominant in controls. It was inferred that genotype GG positive individuals at position −308 of TNF-α were susceptible to RA while genotype AA might has a protective effect on RA susceptibility in Saudis. Whereas GG and AA genotype of TNF-β at +252 position might exert additive susceptibility to RA and GA might be refractory. However, there was no significant association between duration of morning stiffness, RF positivity and number of joints involved and distribution of alleles/genotypes of TNF-α (–308) or TNF-β (+252) polymorphism. It may be concluded that the TNF-α (–308) and TNF-β (+252) polymorphisms might influence the susceptibility to RA in Saudi population. These results might have prognostic value for future clinical observations.