BACKGROUND: IQGAP3 is a novel scaffold protein involved in inflammatory and metabolic regulation and may contribute to atherosclerosis. However, its clinical significance in coronary artery disease among patients with type 2 diabetes mellitus (T2DM) remains unclear. This study investigated the association between serum IQGAP3 and coronary lesion severity and evaluated the diagnostic value of combining IQGAP3 with the triglyceride glucose-body mass index (TyG-BMI). METHODS: This prospective study enrolled T2DM patients undergoing coronary angiography. Serum IQGAP3 levels were measured by enzyme-linked immunosorbent assay, and TyG-BMI was calculated using routine clinical parameters. Coronary lesion severity was assessed using the Gensini score and categorized by tertiles. Multivariable logistic regression, restricted cubic spline (RCS), subgroup, and interaction analyses were performed. ROC curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to assess model performance. RESULTS: A total of 392 patients were included. Serum IQGAP3 levels and TyG-BMI increased significantly across Gensini score tertiles (all P< 0.05). Both IQGAP3 (OR = 3.119, 95% CI: 2.049-4.747, P< 0.001) and TyG-BMI (OR = 1.012, 95% CI: 1.003-1.021, P = 0.006) were independently associated with severe coronary stenosis. Adding TyG-BMI to the traditional risk factor model improved discrimination (AUC: 0.702 vs. 0.753; NRI = 0.180, IDI = 0.065; both P< 0.001). Further incorporation of IQGAP3 increased the AUC to 0.803 and significantly improved reclassification (NRI = 0.307, IDI = 0.138; both P< 0.001), with optimism-corrected internal validation demonstrating an AUC of 0.788 and a calibration slope of 0.926. RCS analyses demonstrated a linear positive association between IQGAP3 and disease risk, whereas TyG-BMI exhibited a nonlinear relationship. Subgroup analyses showed consistent associations across most clinical strata. Age significantly modified the association between IQGAP3 and severe coronary stenosis (Pinteraction = 0.036), with a stronger effect observed in patients younger than 65 years. CONCLUSION: Serum IQGAP3 and TyG-BMI are independently associated with coronary lesion severity in T2DM patients. Their combined assessment provides incremental discriminative value for coronary lesion severity and may serve as a practical, non-invasive tool for cardiovascular risk stratification.