Background <p>The Endothelial Activation and Stress Index (EASIX) serves as a biomarker of endothelial dysfunction. Although EASIX is prognostic in critical illnesses such as sepsis, its specific association with mortality in critically ill patients with diabetes mellitus (DM) is undetermined. This study was designed to evaluate this relationship.</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) and analyzed as log2-transformed values and by tertiles. The primary outcome was 30-day mortality, with 365-day mortality as a secondary outcome. Cox proportional hazards regression, Kaplan-Meier analysis, restricted cubic splines, subgroup analyses, and mediation analysis with lactate as a mediator were employed to evaluate the prognostic association. Sensitivity analyses, including propensity score matching, were performed to assess the robustness of the findings.</p> Results <p>This study included 4,175 critically ill patients with DM. After full adjustment, each log2‑unit increase in the EASIX score was associated with a significantly increased risk of both 30‑day mortality (HR 1.20, 95% CI 1.16–1.24) and 365‑day mortality (HR 1.14, 95% CI 1.11–1.17). Mortality risk demonstrated a graded increase across ascending EASIX tertiles. A linear dose‑response relationship was confirmed, and this association remained consistent across most predefined subgroups. Propensity score matching analysis further supported this association. Mediation analysis indicated that lactate levels partially mediated the observed relationship between EASIX and mortality.</p> Conclusions <p>EASIX is independently associated with increased 30‑day and 365‑day mortality in critically ill patients with DM, an effect partially mediated by lactate.</p> Clinical trial number <p>Not applicable.</p>