Background/Objectives: Coronary collateral circulation (CCC) reduces ischemic damage in patients with chronic total occlusion (CTO), yet collateral development varies considerably among individuals. Endothelial stress and systemic inflammation are key biological processes involved in collateral vessel formation. The Endothelial Activation and Stress Index (EASIX), calculated from lactate dehydrogenase, creatinine, and platelet count, is a simple marker reflecting endothelial dysfunction and inflammatory status. However, evidence regarding its relationship with angiographic coronary collateral development in CTO remains limited. Therefore, this study aimed to evaluate the association between EASIX and CCC grades in patients with CTO. Methods: This retrospective study included 186 patients with CTO who underwent coronary angiography. CCC was evaluated using the Rentrop–Cohen classification and categorized as poorly developed (grades 0–1) or well-developed (grades 2–3). Clinical and laboratory data, including EASIX, were collected. Univariate and multivariate binary logistic regression analyses were performed to identify factors associated with poorly developed CCC. EASIX was standardized (z-score), and odds ratios were reported per 1-standard deviation increase. The predictive performance of EASIX was assessed using receiver operating characteristic (ROC) curve analysis. Results: Poorly developed CCC was observed in 70 patients (37.6%). Patients with well-developed CCC had significantly lower EASIX values (median 0.44 vs. 0.67, p < 0.001) and higher HDL cholesterol levels (p = 0.043). Neutrophil-to-lymphocyte ratio was also higher in the poorly developed CCC group (median 2.59 [2.19–3.59] vs. 2.41 [1.59–3.49], p = 0.028). In multivariate analysis, standardized EASIX remained independently associated with poorly developed CCC (OR 2.536 per 1-SD increase, 95% CI 1.734–3.710, p < 0.001). ROC analysis showed that EASIX provided moderate discrimination for poorly developed CCC (AUC 0.718), with 72.9% sensitivity and 62.1% specificity at a cutoff of >0.51. Conclusions: Higher EASIX values were independently associated with poorly developed CCC in patients with CTO. These findings support a link between systemic endothelial stress and impaired collateral vessel formation. EASIX may serve as a simple, practical, and low-cost biomarker to support risk stratification in CTO patients; however, prospective studies are needed to confirm these results and clarify clinical implications.