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Anemia is the most frequent hematologic abnormality among cancer patients. Its pathophysiology comprises reduction in erythrocyte half-life, poor iron reutilization by the bone marrow, and inadequate response to erythropoietin (EPO), with reduced endogenous EPO (eEPO) levels. Current treatment implies the use of erythropoiesis-stimulating agents (ESA), to which 35–48% of patients show primary resistance. The search for predictors of response to ESA treatment has been inconclusive. Iron or vitamin deficiency, the recent need for transfusion, or a lack of hemoglobin increase within the first 2–4 weeks usually predict resistance to ESA. High serum eEPO levels at treatment initiation (> 100–150 mU/ml) may also predict resistance, especially in hematologic malignancies, but the results in solid tumors are not consistent. Although patients with cancer-related anemia show higher eEPO levels than patients without anemia, there is extreme variability among individuals. Future studies are needed to clarify eEPO usefulness in predicting response to ESA treatment.