BACKGROUND: Severe coronary anatomical involvement is clinically important in patients with acute coronary syndrome (ACS), yet evidence on its relationship with insulin sensitivity remains limited. This study examined the association of the single-point insulin sensitivity estimator (SPISE), a simple surrogate marker of insulin sensitivity, with severe coronary anatomical patterns, including left main and/or three-vessel disease and isolated three-vessel disease, in middle-aged and older patients with ACS. METHODS: This cross-sectional analysis was based on data from the CCC-ACS project. A total of 16,383 patients were included in the analysis of left main and/or three-vessel disease, and 13,390 patients were included in the analysis of isolated three-vessel disease. SPISE was analyzed as both a continuous variable and according to tertiles. Multivariable logistic regression was used to evaluate the associations between SPISE and the study outcomes. Restricted cubic spline analyses were performed to assess dose-response patterns, and subgroup and sensitivity analyses were conducted to examine the robustness of the findings. RESULTS: Higher SPISE was associated with lower odds of both severe coronary anatomical outcomes. In the fully adjusted model, each 1-unit increase in SPISE was associated with lower odds of left main and/or three-vessel disease (OR, 0.977; 95% CI, 0.957-0.998) and isolated three-vessel disease (OR, 0.957; 95% CI, 0.935-0.980). Compared with patients in the lowest SPISE tertile, those in the highest tertile had lower odds of both outcomes. Restricted cubic spline analyses supported dose-response relationships. Subgroup analyses suggested age-related heterogeneity, with the inverse associations mainly observed in patients aged <65 years and attenuated among those aged ≥65 years. Sensitivity analyses yielded generally consistent results. CONCLUSION: Among ACS patients aged 45 years or older, higher SPISE was associated with lower odds of severe coronary anatomical involvement, with this association mainly evident in patients aged <65 years. These findings support a potential link between reduced insulin sensitivity and angiographically defined severe coronary anatomical involvement and suggest that SPISE may serve as a readily available marker for identifying patients more likely to have high-risk coronary anatomy.