Background: Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory illness. Proinflammatory cytokines play a crucial role in the development of RA by inducing an inflammatory response. One of these cytokines is interleukin-21 (IL-21), which regulates B-cell proliferation, plasma differentiation, and immunoglobulin synthesis; consequently, IL-
21's actions on B cells may take part in the development of autoimmune disorders. Aim of the study: to investigate the association between plasma IL-21 gene polymorphism and susceptibility to RA in Egyptian patients and to find out its relation to disease activity. Methods: The case-control study was performed on 100 subjects; divided into two groups: Group(I):70 RA patients, Group (II):30 healthy matched controls. Through history taking, clinical examination and assessment of IL-21 gene rs2055979 by quantitative Real-Time PCR (qRT-PCR). Evaluation of disease activity by using the Disease Activity Score (DAS-28 score). Results: RA patients were significantly associated with a higher frequency of rs2055979 AA genotype and A allele (p= 0.023, 0.028) with risk to RA development (OR=2.759, 2.040 respectively). IL-21 genotypes AA and CA were significantly associated with higher DAS-28 when compared to the CC genotype (p≤0.05). On regression analysis, IL21 dominant models were considered independent risk predictors of higher RA disease activity (