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Background: The endothelial activation and stress index (EASIX), derived from the serum lactate dehydrogenase, creatinine, and platelet counts, is a composite biomarker for endothelial dysfunction and systemic stress. It has been developed to predict clinical outcomes in hematologic malignancies. This study aimed to investigate the EASIX’s predictive role in contrast-induced nephropathy (CIN) and in-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods: A total of 1552 patients with STEMI who underwent primary PCI were retrospectively included. The patients were divided into two groups: CIN (+) and CIN (−). Baseline demographic, laboratory, clinic, and procedural variables were compared between the two groups. Logistic regression analysis was performed to identify independent predictors of CIN and in-hospital mortality, while receiver operating characteristic (ROC) curves were used to determine the optimal EASIX cut-off values. Results: CIN developed in 7.6% (n = 118) of the study population, and these patients had significantly increased EASIX scores. Those with CIN were older and exhibited higher rates of diabetes mellitus, chronic kidney disease (CKD), and decreased left ventricular ejection fraction (LVEF) (all p < 0.001). In multivariable analysis, age (OR 1.053), CKD (OR 1.338), reduced LVEF (OR 0.965), and EASIX (OR 2.467) independently predicted CIN. EASIX > 0.93 demonstrated strong discriminatory ability (AUC 0.785; sensitivity 72% and specificity 72%). EASIX also independently predicted in-hospital mortality (OR 3.592), with an optimal cut-off > 0.88 (AUC 0.774). Conclusions: By integrating markers of renal function, endothelial activation, and systemic stress, EASIX may serve as a useful and reliable indicator for predicting CIN development and in-hospital mortality in STEMI patients undergoing primary PCI.