Rheumatoid arthritis (RA) may be impacted by HLA-G gene variation. In a group of Egyptian RA patients, this study sought to determine the effects of the polymorphisms +3142G>C and 14 bp ins/del on disease susceptibility, activity, severity, and response to treatment. Methods: This case-control study was done on 75 patients with RA and 75 healthy subjects. The HLA-G rs1063320 (+3142G>C) and rs66554220 14 bp insertion (ins)/deletion (del) variants were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFP) and PCR method, respectively. Results: Our finding didn't support an association between HLA-G 14 bp ins/del or the HLA-G +3142G>C variants and RA susceptibility. The G allele of HLA-G +3142G>C was significantly associated with the presence of subcutaneous nodules and longer morning stiffness. The GG genotype and the G allele of HLA-G +3142G>C were shown to be a risk factor for higher C-reactive protein (CRP) and autoantibodies production [anti-citrullinated protein antibodies (ACPA) and ACPA+ rheumatoid factor (RF)].The HLA-G+3142G>C polymorphism was found to be associated with RA severity (higher rheumatoid arthritis severity scale ,RASS, scores). Conclusion: The 14 bp ins/del and the +3142G>C of HLA-G gene didn't appear to be associated with RA susceptibility in this studied group of RA patients, but may act as a genetic modifier of disease phenotype in terms of autoantibody production, severity, clinical phenotype and treatment response. In this sense, we suggest that these polymorphisms act as a disease modifier rather than a risk factor for development of RA.