The appearance of nucleated red blood cells (NRBC) in the circulation is associated with a variety of severe diseases, and indicates a relatively poor prognosis. Whether a malfunction of the bone marrow leads to this phenomenon is as unknown as the possible role that cytokines could play in this process. We analyzed erythropoietin, interleukin (IL)-3, IL-6, and IL-12p70 in the blood of 301 patients with circulating NRBCs. Two hundred fifty NRBC-negative patients served as controls. Multiple logistic regression revealed a significant association between the appearance of NRBCs in the blood and erythropoietin (odds ratio, 1.017; 95% confidence limits, 1.007-1.027; P < 0.001), IL-3 (odds ratio, 1.293; 95% confidence limits, 1.180-1.417; P < 0.001), IL-6 (odds ratio, 1.138; 95% confidence limits, 1.016-1.275; P < 0.05), and age (odds ratio, 1.019; 95% confidence limits, 1.009-1.030; P < 0.001), respectively. Gender and IL-12p70 were not significantly associated with the appearance of NRBC in the blood. To estimate the RBC production in the bone marrow, the increase in the reticulocyte concentration in blood was measured. The reticulocyte concentration in NRBC-positive patients was 69 ± 2/nL, which was significantly higher than in NRBC-negative patients (60 ± 2/nL; P < 0.01). Taken together, NRBC could be a marker that sums up hypoxic and inflammatory injuries. Thus, generally, the appearance of NRBC in blood is a valid parameter to identify patients at high mortal risk. Moreover, the increased number of reticulocytes in the blood of NRBC-positive patients may indicate that the appearance of NRBC is not associated with disturbed bone marrow function as far as the erythropoiesis is concerned.