Background <p>Interleukin (IL)-32 and IL-37 are implicated in the pathophysiology of rheumatoid arthritis (RA). The aim of this study is to investigate serum levels and the genotypes of the IL-32 and IL-37 variants (IL-32 (rs28372698) and IL-37 (rs3811047)) in RA patients compared to controls and to evaluate the relation between these variables and RA disease parameters.</p> Methods <p>Forty-seven RA patients who fulfilled the 2010 ACR diagnostic criteria of rheumatoid arthritis and 44 controls were included in the study. Measurement of serum IL-32 and IL-37 levels was performed using human IL-32 and human IL-37 enzyme-linked immunosorbent assay (ELISA)s. Genotyping of the IL-32 and IL-37 variants (IL-32 (rs28372698) and IL-37 (rs3811047)) was done by real-time polymerase chain reaction.</p> Results <p>Significant elevations in serum levels of IL-32 and IL-37 in RA patients were found compared to controls, but no significant difference in genetic variants. Serum levels of IL-37 were statistically significantly lower in RA patients treated with corticosteroids. A statistically significant association was found between the TT genotype of IL-32 and higher disease activity and extra-articular manifestations. Additionally, a statistically significant association was found between the AA genotype of IL-37 in RA patients and joint deformities.</p> Conclusion <p>RA patients have higher serum levels of IL-32 and IL-37 compared to healthy controls, making them potential diagnostic indicators. However, no correlation was found between these serum levels and the inflammatory markers, the RA disease activity, or the lipid profile in RA patients. The TT genotype of IL-32 and the AA genotype of IL-37 were associated significantly with high disease activity, extra-articular manifestations, and deformities. These findings emphasize the need for closer follow-up for RA patients carrying the genotypes to avoid unfavorable outcomes.</p>