BACKGROUND: The single-point insulin sensitivity estimator (SPISE) is a novel metric used to assess insulin resistance. However, its association with collateral circulation impairment in patients with chronic total occlusion (CTO) remains unclear. This study aims to investigate the relationship between SPISE, high-sensitivity C-reactive protein (hs-CRP), and collateral circulation impairment. METHODS: Logistic regression models, restricted cubic spline (RCS) models, and subgroup analyses were utilized to explore the associations between SPISE, hs-CRP, and collateral circulation impairment. The predictive capability was evaluated using receiver operating characteristic (ROC) curves. Both base and extended models were constructed, and the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices were calculated to assess the incremental predictive value of the additional biomarkers. A mediation effect model was employed to analyze the mediating role of hs-CRP in the relationship between SPISE and collateral circulation impairment. Additionally, the proportional scaling method was used to determine the weights of SPISE and hs-CRP, and a composite score was developed for sensitivity analysis. RESULTS: A total of 362 participants were included in this study. After adjusting for all covariates, SPISE was negatively associated with collateral circulation impairment (OR = 0.371, 95% CI 0.245-0.543, P<0.001), while hs-CRP was positively associated with collateral circulation impairment (OR = 2.133, 95% CI 1.617-2.872, P<0.001). These associations remained consistent across most subgroups, with both SPISE and hs-CRP showing a linear relationship with collateral circulation impairment. The area under the curve (AUC) for SPISE in predicting collateral circulation impairment was 0.730 (95% CI 0.677-0.782), and the AUC for hs-CRP was 0.739 (95% CI 0.685-0.795). After adding SPISE and hs-CRP to the base model, the predictive ability of the extended model significantly improved, with the AUC increasing from 0.763 (95% CI 0.713-0.814) to 0.872 (95% CI 0.835-0.908). The continuous NRI was 0.794 (95% CI 0.592-1.096) and the IDI was 0.197 (95% CI 0.127-0.284). Mediation analysis indicated that hs-CRP partially mediated the relationship between SPISE and collateral circulation impairment, with a mediation proportion of 27% (P<0.001) after multivariable adjustment. Sensitivity analysis incorporating the SPISE-hs-CRP composite score into the base model to construct the extended model yielded consistent results. CONCLUSIONS: The SPISE and hs-CRP are not only significantly associated with the risk of collateral circulation impairment, but their inclusion in the base model also leads to a significant improvement in the model's risk stratification ability.