Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease caused by the interplay of hereditary and environmental factors. Extreme polymorphism is assumed for the Endoplasmic Reticulum Aminopeptidase 1 Gene Polymorphism (ERAP1) gene. ERAP1 single-nucleotide polymorphisms (SNPs) profoundly modify its immunological, clinical, and biochemical features. The study aims to ascertain how ERAP1 Gene single-nucleotide polymorphisms (SNPs) affect RA susceptibility, disease activity, and severity. Methods: The study enrolled 98 subjects, 49 RA patients, and 49 healthy volunteers. Real-time PCR was used to genotype all subjects for the ERAP1 SNPs (rs27037, rs27044, and rs30187). Results: With reference to rs27037, the T allele, the TT, and GT genotypes were linked to an increased risk of RA (P < 0.001, P 0.006, and P 0.002, respectively). In relation to rs30187, RA risk was higher in those with TT, CT, and T alleles than in the healthy controls. The risk genotypes TT and GT of rs27037 (P 0.02 and P 0.03, respectively) were linked to anticitrullinated antibody seropositivity. On the other hand, the risk genotypes TT and CT of rs30187 were associated with rheumatoid factor seropositivity (P<0.001 for both). Conclusions: Our study showed that rs27037 and rs30187, two ERAP1 SNPs, increase the incidence of seropositive RA.