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"nBackground: There are several evidences that genetic factors besides environmental triggers have important role in initiating the rheumatoid arthritis (RA). The aim of this study was to investigate the association of rheumatoid arthritis with different subtypes of HLA DR4 in Iranian patients. "nMethods: In an un-matched case control study, 110 rheumatoid arthritis patients (case) and 56 knee osteoarthritis patients (control) of outpatient clinic in Shariati Hospital were entered to the study. After blood sampling from case and control groups, DNA was isolated by using salting-out method and HLA DR4 and its subtypes were detected. Association of HLA DR4 and its subtypes with rheumatoid arthritis, rheumatic factor and clinical manifestations of diseases was evaluated. "nResults: Eighty nine (80.9%) of rheumatoid arthritis patients were female and 21 were male. Thirty four of the RA patients (30.9%) and eleven subjects from the control group (19.6%) were HLA DR4 positive (p=0.12). The most frequent subtype of HLA DR4 in RA patients was 0404 and in control group was 0401 (p=0.03). There were not statistically significant association between HLA DR4 and age of disease onset, family history, morning stiffness and rheumatoid factor. Joint swelling and tenderness had association with HLA DR4 (p=0.04 and p=0.03). "nConclusion: Although there were no statistically significant association between rheumatoid arthritis and HLA DR4, but prevalence of this HLA was higher in patients than control. It is possible that in some ethnics, other HLAs may have role in pathogenesis of disease.