BACKGROUND: Nucleated red blood cells (NRBCs) in the blood of critically ill patients are associated with increased mortality. The predictive value of NRBCs among septic critically ill patients remains indistinct. The aim of the present analysis was to evaluate the predictive validity of NRBCs in septic critically ill patients. METHODS: Data from septic critically ill patients were collected between 2020 and 2023. Daily NRBC values were recorded, and their predictive validity for mortality was statistically analysed. A cut-off level based on the maximum NRBC value during the patients' intensive care unit (ICU) stay was determined using ROC analysis and Youden's method. Survival was depicted using Kaplan-Meier curves. RESULTS: 465 septic critically ill patients were analysed. Patients who died had significantly higher maximum NRBC values during their ICU stay compared to survivors (290/µL [60/2010] vs. 30/µL [10/170]; p < 0.001). A cut-off of maximum NRBCs of ≥100/µL effectively divided the study population into two groups with the most significant difference in ICU mortality (AUC 0.745; 95% CI 0.693-0.797; p < 0.001). Increased maximum NRBC values of ≥100/µL were associated with fivefold higher odds of death (odds ratio [OR] 5.03; 95% CI 3.19-7.90; p < 0.001). Higher mortality rates were confirmed using a Cox proportional-hazards model (hazard ratio [HR] 1.84; 95% CI 1.16-2.98; p = 0.012). CONCLUSIONS: Measuring NRBCs can help predict mortality in septic critically ill patients with high prognostic accuracy. A cut-off of ≥100/µL for NRBCs appears to effectively stratify the study population regarding mortality.