Background <p>Interleukin-37 (IL-37) is an anti-inflammatory cytokine with emerging roles in immune regulation and tumor biology. Its functional interaction with the single immunoglobulin IL-1-related receptor (SIGIRR) has been implicated in modulation of inflammatory signaling pathways that may influence leukemogenesis. However, the clinical significance of the IL-37/SIGIRR axis in acute myeloid leukemia (AML) remains insufficiently explored. The present study explored their potential associations with clinical characteristics, molecular mutations and treatment outcomes to determine their utility as potential prognostic biomarkers in the studied population.</p> Methods and Results <p>This study enrolled 50 newly diagnosed adult patients with AML and 50 age and sex matched healthy controls. Expression levels of IL-37 and SIGIRR mRNA were quantified using reverse transcription quantitative polymerase chain reaction (RTqPCR). Both IL-37 and SIGIRR mRNA expression levels were significantly downregulated in patients with acute myeloid leukemia (AML) compared to healthy controls (<i>p</i> = 0.011 and <i>p</i> &lt; 0.001, respectively). Notably, patients with refractory disease exhibited significantly lower expression levels of both markers compared to those who achieved complete remission (<i>p</i> = 0.006 and <i>p</i> &lt; 0.001, respectively).</p> Conclusions <p>The present findings indicate that down-regulation of IL-37 and its receptor SIGIRR is associated with poor therapeutic response in AML. These results suggest that the IL-37/SIGIRR axis represents a potential prognostic biomarker and may contribute to immune-mediated mechanisms involved in AML progression. Further large-scale studies are warranted to validate these findings and to explore the potential of targeting this pathway as a novel immunomodulatory therapeutic strategy in AML.</p>