Background <p>Endothelial activation and stress index (EASIX), a biomarker of endothelial dysfunction, has been established as a prognostic tool in critical illnesses like sepsis. However, its role in critically ill patients with ischemic stroke (IS) has not been determined. This study aimed to investigate the relationship between EASIX and mortality in this population.</p> Methods <p>This retrospective study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC IV) database. EASIX was calculated as lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelet count (10⁹/L). Patients were stratified into tertiles based on log₂-transformed EASIX values. The study outcomes were 30-day and 365-day mortality. Cox proportional hazards models, Kaplan–Meier survival curves, restricted cubic splines, and subgroup analysis were used to evaluate the prognostic value of EASIX.</p> Results <p>The study cohort comprised 1,238 critically ill patients with ischemic stroke, of whom 53.2% were male and the median age was 70.6&#xa0;years. After full adjustment, each log2-unit increase in EASIX was significantly associated with higher risks of 30-day (HR 1.14, 95% CI 1.07–1.21) and 365-day mortality (HR 1.12, 95% CI 1.06–1.18). Mortality increased gradedly across log2(EASIX) tertiles, with the highest tertile exhibiting a 91% higher risk of 30-day mortality (HR 1.91, 95% CI 1.35–2.69) and a 78% higher risk of 365-day mortality (HR 1.78, 95% CI 1.37–2.32) compared with the lowest tertile. A linear dose–response relationship was confirmed, and the association remained consistent across most subgroups, although it appeared more pronounced in patients without hypertension and without atrial fibrillation.</p> Conclusions <p>Higher EASIX is independently associated with increased 30-day and 365-day mortality in ICU-admitted patients with ischemic stroke.</p>