The presence of nucleated red blood cells (NRBCs) in the blood of patients with a variety of severe diseases is known to be highly associated with increased mortality. Blood analyzers to routinely measure NRBC concentrations are now available. However, the prognostic significance of such measurements has not been evaluated. Using a Sysmex XE-2100 (Sysmex; Norderstedt, Germany), we measured NRBC concentrations in 15,541 blood samples from 4,173 patients at a university clinic over the course of 12 weeks. NRBCs were found at least once in 7.5% of all patients. The highest incidence (20.0%) was found in patients from the intensive care unit of the general and accident surgery. The incidence of NRBC increased with age. The mortality of NRBC-positive patients (n = 313) was 21.1% (n = 66); this was significantly higher (P <.001) than the mortality of NRBC-negative patients (1.2%, n = 3,860). Mortality increased with increasing NRBC concentration. With regard to in-hospital mortality, NRBCs in blood showed sensitivity and specificity of 57.9% and 93.9%, respectively. NRBCs were detected for the first time, on average, 21 days (median 13 days) before death. The routine analysis of NRBCs in blood is of high prognostic power with regard to in-hospital mortality. This parameter may serve as an early indicator of patients at increased risk.