Background. The mortality of intensive care unit (ICU) patients ranges from 5% to 30%, and nucleated red blood cells (NRBCs) were revealed to be related to mortality. However, few studies have discussed the causes of NRBC or compared the dynamic count among patients with underlying diseases. Aim. To explore the possible causes of NRBC in ICU patients and the dynamic trends between survival and death groups and underlying disease subgroups. Methods. A total of 177 ICU patients were retrospectively included. The possible causes of NRBC in ICU patients were discussed. The relationship between NRBC and in-hospital mortality and the dynamic trend of NRBC during hospitalization between the survival and death groups and underlying disease subgroups were compared. Results. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score in the NRBC-positive group were higher (23.52 ± 9.39 vs. 19.62 ± 7.59; 13.50 (9.00–17.50) vs. 8.00 (6.00–12.00)). Red blood cell count (RBC), hemoglobin (Hb) level, oxygen saturation (SO2), oxygenation index (OI), and serum protein level were lower in the NRBC-positive group. However, D-dimer (D-D), liver and kidney function indices, lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin (PCT) were higher than those in the NRBC-negative group. Correlation analysis showed that NRBC count was positively correlated with alkaline phosphatase (ALP) and red blood cell distribution width (RDW) and negatively correlated with SO2 (r = 0.431, P < 0.05 ; r = 0.363, P < 0.05 ; r = −0.335, P < 0.05 ). The mortality rate in the NRBC-positive group was higher, and the median survival time was shorter than that in the NRBC-negative group (77.9% vs. 95.7%, P < 0.001 ; 15 days vs. 8.5 days, P < 0.01 ). Univariate and multivariate Cox regression analyses showed that NRBC was an independent risk factor for in-hospital mortality (HR: 1.12 (1.03–1.22), P < 0.01 ). The NRBC count had different hazard ratios (HRs) for in-hospital mortality in the subgroups. Locally weighted scatterplot smoothing (LOWESS) analysis revealed that the NRBC count in the death group was higher and had a sharp upward trend before death, whereas that in the survival group was negative or stayed at a low level. The changing trend of the NRBC count was different in patients with different underlying diseases. Conclusion. The possible cause of NRBC in ICU patients was related to inflammation and hypoxia. The persistently high level and rapid upward trend of NRBC counts are risk factors for in-hospital mortality in ICU patients. The changing trend of the NRBC count varied in patients with different underlying diseases.