Endothelial Activation and Stress Index (EASIX) is a reliable alternative biomarker of endothelial dysfunction. Because endothelial activation is involved in sepsis pathophysiology, we aimed to investigate the association between EASIX and prognosis in septic patients. Data were extracted from the Medical Information Mart for Intensive Care (MIMIC) IV database. EASIX scores were calculated using the formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelet count (10/L). Patients were grouped into tertiles according to log2 transformed EASIX. The primary and secondary outcomes were 28-day and 90-day mortality. Cox proportional hazards models, Kaplan-Meier curves, restricted cubic spline curves, and subgroup analyses were conducted to evaluate the association between EASIX and prognosis in septic patients. A total of 7504 patients were included. Multivariable Cox proportional hazards analyses showed that higher log2-EASIX was associated with increased risk of 28-day mortality (HR, 1.10; 95% CI, 1.07-1.13; < 0.001). Compared with tertile 1, the tertile 2 and 3 groups had higher risk of 28-day mortality [HR (95% CI) 1.24 (1.09-1.41); HR (95% CI) 1.51 (1.31-1.74)]; for trend < 0.001). Similar results were found for 90-day mortality. Kaplan-Meier curves showed that patients with higher EASIX had lower 28-day and 90-day survival rates. A linear relationship was found between log2-EASIX and 28-day and 90-day mortality. High EASIX was significantly associated with an increased risk of 28-day and 90-day all-cause mortality in patients with sepsis.