Background: Cytokines are integral to the pathogenesis of rheumatoid arthritis (RA). Joint inflammation is attributed to an imbalance between inflammatory and anti-inflammatory cytokines. Polymorphism of cytokine genes that affect their levels of expression may serve as predictive biomarkers for therapeutic response. This study examined the relationship between RA susceptibility and selected SNPs of TNF-α 308, TGF-β, IL-6, IL-10, and IFN-γ genes, as well as their potential as predictors of methotrexate therapy response. Methods: This case-control study involved 96 rheumatoid arthritis patients and 96 healthy individuals. Genotyping was carried out by polymerase chain reaction sequence specific primer (PCR-SSP). Results: TNF-α (308) GA, IFN- γ (874) TT and IL-6 (174) GC genotypes were significantly associated with elevated risk of RA (p=0.02, p=0.04, p=<0.001, respectively). Moreover, TGF-β codon 10 T allele and IL- 10 (1082) A allele were considered risk alleles for RA (p<0.001 & p=0.001, respectively). No association was found between TGF-β codon 25, IL-10 (819) and IL-10 (592) SNPs and the risk for RA. Regarding therapeutic outcome, worse outcome was linked to IL-6- (174) C, TNF-α- (308) G, TGF-β- codon 10 C, IL- 10- (1082) G, IL-10- (819) C and IL-10- (592) C alleles (p=0.02, p=0.02, p=0.01, p=0.001, p=0.01 & p=0.02, respectively). Conclusion: Our findings imply that the examination of cytokine-encoding gene polymorphisms could be beneficial to determine RA susceptibility and predicting the outcome of methotrexate therapy in Egyptian RA patients.