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Anemia is very common in patients with chronic diseases. To determine the role of increased red blood cell (RBC) turnover in such subjects, we estimated RBC survival in three groups of chronically ill patients using a simple technique in which RBC life span is estimated via measurements of breath carbon monoxide concentration. The study groups consisted of subjects with: (1) osteoarthritis, (2) rheumatoid arthritis, and (3) anemia who were hospitalized for treatment of a variety of chronic illnesses. None of the anemic subjects had evidence of hemorrhage, a deficiency state, or a marrow abnormality to account for their reduced hemoglobin concentration. Subjects with osteoarthritis had a mean RBC life span (127 ± 25 days) that did not differ significantly from normal (122 ± 23 days). In contrast, RBC life span was significantly reduced (P < 0.001) in both the rheumatoid arthritis subjects (90 ± 15 days) and the anemic, hospitalized patients (87 ± 33 days). The hemoglobin concentration of the rheumatoid patients was near normal (13.5 ± 1.5 g/dl), indicating that the marrow was compensating for the reduced RBC life span, whereas no such compensation was apparent in the anemic, chronically ill subjects. We conclude that a modest (approximately 25%) reduction in RBC life span commonly occurs in patients with chronic disease, and this reduction becomes clinically relevant in subjects whose marrow cannot respond with increased RBC output. Am. J. Hematol. 81:432-438, 2006. © 2006 Wiley-Liss, Inc.