ObjectiveThis research aims to investigate the prognosis value using the time-weighted average neutrophil-to-lymphocyte ratio (TWA-NLR) for predicting all-cause hospital mortality among sepsis patients. Data were analyzed through the use of the eICU Collaborative Research Database (eICU-CRD 2.0) as well as Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2). MethodsSeptic patients from both eICU-CRD 2.0 as well as MIMIC-IV 2.2 databases were included. The neutrophil-to-lymphocyte ratios (NLR) were available for analysis, utilizing complete blood counts obtained on days one, four, and seven following ICU admission. The TWA-NLR was computed at the end of the seven days, and patients were then stratified based on TWA-NLR thresholds. 90-day all-cause mortality during hospitalization was the primary objective, with 60-day all-cause hospital mortality as a secondary objective. The correlation between TWA-NLR and sepsis patients' primary outcome was analyzed using univariable and multivariable Cox proportional hazard regressions. A restricted cubic spline (RCS) analysis was conducted in an attempt to confirm this association further, and subgroup analyses were employed to evaluate the correlation across various comorbidity groups. Results3921 patients were included from the eICU-CRD 2.0, and the hospital mortality rate was 20.8 %. Both multivariable as well as univariable Cox proportional hazard regression analyses revealed that TWA-NLR was independently correlated with 90-day all-cause hospital mortality, yielding a hazard ratio (HR) of 1.02 (95 % CI 1.01–1.02, P-value<0.01) as well as 1.12 (95 % CI 1.01–1.15, P-value<0.01), respectively. The RCS analysis demonstrated a significant nonlinear relationship between TWA-NLR and 90-day all-cause hospital mortality risk. The study subjects were divided into higher (>10.5) and lower (≤10.5) TWA-NLR cohorts. A significantly decreased incidence of 90-day all-cause hospital mortality (HR = 0.56, 95 % CI 0.48–0.64, P-value<0.01) and longer median survival time (40 days vs 24 days, P-value<0.05) were observed in the lower TWA-NLR cohort. However, septic patients with chronic pulmonary (interaction of P-value = 0.009) or renal disease (interaction of P-value = 0.008) exhibited significant interactive associations between TWA-NLR and 90-day all-cause hospital mortality, suggesting the predictive power of TWA-NLR may be limited in these subgroups. The MIMIC-IV 2.2 was utilized as a validation cohort and exhibited a similar pattern. ConclusionOur findings suggest that TWA-NLR is a powerful and independent prognostic indicator for 90-day all-cause hospital mortality among septic patients, and the TWA-NLR cutoff value may prove a useful method for identifying high-risk septic patients.