Background: Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by joint destruction, chronic inflammation, and autoantibody production. IL-21 plays an essential role in the immunopathology of RA. The aim of the study: was to investigate the association between plasma interleukin-21 gene polymorphism and the susceptibility to rheumatoid arthritis in Egyptian patients and to find out its relation to disease activity. Methods: This case control study was conducted on 100 subjects; divided into two groups:Group(I):70 RA patients,Group(II):30 apparently healthy matched subjects.Through history taking, clinical examination and assessment of IL-21 gene rs2055979 by quantitative Real Time PCR (qRT-PCR).Disease activity was evaluated using DAS-28 score. Results: RA patients were significantly associated with higher frequency of rs2055979 AA genotype and A allele (p= 0.023, 0.028 respectively) with risk to develop RA.IL-21 genotypes AA and CA were significantly associated with higher DAS-28 when compared to CC genotype (p≤0.05). Conclusion: Our results showed that genetic alterations in the IL-21 gene are associated with susceptibility to rheumatoid arthritis in the Egyptian population.