Abstract: Objective To investigate the prognostic value of endothelial activation and stress index (EASIX) for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL).Methods A total of 580 patients who were diagnosed with DLBCL in six medical centers in Huaihai Lymphoma Working Group from August 2008 to March 2022 were selected and their clinical data were retrospectively analyzed. The MaxStat algorithm was used to determine the optimal cut-off value of EASIX. The Cox proportional hazard regression model was used for univariate and multivariable analysis to determine the variables influencing the survival outcomes of DLBCL patients. Kaplan-Meier survival curves were plotted for prognostic analysis, and the differences between groups were tested by log-rank.Results There were 294 men among the 580 patients(50.7%). The median age was (60.32±13.36) years, and the overall 5-year OS rate was 56.4%. Through MaxStat statistics, the optimal cut-off value of EASIX was 1.17. Multivariable analysis indicated that EASIX, age, hemoglobin, central involvement and Ann Arbor stage were the independent risk factors for DLBCL patients (P<0.05). The results of subgroup analysis showed that EASIX-based re-stratification was suitable for evaluating the prognosis of patients in the BCL-2- and BCL-2+ groups, the BCL-6- and BCL-6+ groups, the GCB and non-GCB groups, the ECOG PS < 2 and ≥ 2 groups, the Ann Arbor stages Ⅰ/Ⅱ and Ⅲ/Ⅳ, the IPI score LR/LIR and HIR/HR groups, and the NCCN-IPI score LR/LIR and HIR/HR groups.Conclusions High EASIX(>1.17) is associated with poor prognosis for patients newly diagnosed with DLBCL, and EASIX can accurately stratify the prognosis of patients in different subgroups.