Background and aims <p>To investigate the correlation between tumor-specific growth factor (TSGF) and the presence of coronary artery disease (CAD) in individuals with type 2 diabetes mellitus (T2DM).</p> Methods and results <p>Data from a total of 223 subjects with T2DM were cross-sectionally analyzed. Serum TSGF concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) in both CAD-positive and CAD-negative subjects. Logistic regression analysis was used to assess the association between TSGF and CAD, while controlling for major risk factors. The predictive power of TSGF for CAD was determined through receiver operating characteristic (ROC) curve analysis. Among the 223 subjects, 136 had no CAD and 87 exhibited clinically significant CAD. The median serum TSGF level was significantly higher in the CAD group (66.8 U/ml) compared to the non-CAD group (59.4 U/ml; <i>p</i> &lt; 0.001). Binary logistic regression, adjusted for major risk factors, confirmed a strong association between TSGF and CAD (<i>p</i> &lt; 0.001). The ROC analysis identified an optimal TSGF cutoff of 62.5 U/ml, with a sensitivity of 70.1% and a specificity of 64% in predicting CAD in T2DM patients.</p> Conclusion <p>The results showed a significant increase in TSGF levels in CAD patients with T2DM. These findings suggest that TSGF could be a promising biomarker for CAD diagnosis in T2DM patients, and further research is warranted to evaluate its clinical utility.</p> Clinical trial number <p>Not applicable.</p>