Objective <p>Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by persistent inflammation and joint pain. However, the pathogenesis of RA remains incompletely understood. The aim of this study was to investigate the interaction between HLA alleles and immune factors in relation to the risk of RA.</p> Methods <p>Linear regression model was used to assess the association between 133 HLA alleles (with gene frequencies &gt; 1%) and RA. Additionally, we evaluated the potential effects of interactions between HLA alleles and 26 simple immune indicators, as well as four composite immune indicators, on the risk of RA. All analyses were grouped by gender to further explore the potential impact of gender on HLA alleles and immune indicators in RA risk.</p> Results <p>The results showed 37 HLA alleles significantly associated with RA. In the subgroups, 17 and 29 HLA alleles were significantly associated with RA in males and in females, respectively. We identified 44 significant interactions between human leukocyte antigen (HLA) alleles and immune indicators on RA. Further, sex-stratified analyses identified 37 and 45 associations between HLA alleles × immune indicators and RA in males and in females, respectively.</p> Conclusion <p>This study identified interactions between various HLA alleles and immune indicators that may increase or decrease the risk of RA. These findings may further advance the study of immune genetic factors in RA and contribute to the clinical assessment of RA by HLA alleles and various immune indicators.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p>Key points</p> <p>• Associations between HLA alleles and RA were analyzed.</p> <p>• The interactions between HLA alleles and immune indicators in RA risk were explored.</p> </entry> </row> </tbody> </tgroup> </Table></p>