Background: Rheumatoid arthritis (RA) is an autoimmune inflammatory joint disease that causes persistent inflammation, joint deterioration, severe damage, and restricted mobility. Its definite cause is unknown, but genetic and environmental factors are contributory. The study aimed to determine the association of SLC22A4 polymorphism with the severity of rheumatoid arthritis in Zagazig University Hospitals. Methods: Thirty four RA cases diagnosed according to the criteria of the American College of Rheumatology (ACR) and 34 normal controls were enrolled in this study. All cases have given consent and detailed history. Clinical examination, plain x ray and laboratory investigations including erythrocyte sedimentation rate, C-reactive protein, anti-cyclic-citrullinated peptide antibodies and rheumatoid factor were performed. Disease activity score-28 (DAS-28) was assessed. The SLC22A4 slc2F1 (rs2073838) and slc2F2 (rs3792876) polymorphisms were genotyped by direct sequencing. Results: The distribution of A alleles of slc2F1 genotype in RA patients were two times than in control while distribution of T alleles of slc2F2 genotype in RA patients were three times than in control but the difference was statistically non-significant (p > 0.05). No significant association between radiographic damage and slc2F1/slc2F2 genotypes and alleles. Conclusions: SLC22A4 variants, particularly slc2F1/slc2F2, does not affect RA susceptibility or severity in the studied RA patients as there were no significant differences in genotypic or allelic frequencies between RA patients and controls.