BACKGROUND Anemia is a common problem in critically ill patients. The etiology of anemia of critical illness is often determined to be multifactorial in the clinical setting, but the pathophysiology remains to be elucidated. Erythropoietin (EPO) is an endogenous glycoprotein hormone that serves as the primary stimulus for erythropoiesis. Recent evidence has demonstrated a blunted EPO response as a factor contributing to anemia of critical illness in specific subsets of patients. Critically ill patients requiring mechanical ventilation who exhibit anemia have not been the subject of previous studies. Our goal was to evaluate the erythropoietic response to anemia in the critically ill mechanically ventilated patient. METHODS A prospective observational study was undertaken in the medical intensive care unit of a tertiary care, military hospital. Twenty patients admitted to the medical intensive care unit requiring mechanical ventilation for at least 72 hours were enrolled as study patients. EPO levels and complete blood count were measured 72 hours after admission and initiation of mechanical ventilation. Admission clinical and demographic data were recorded, and patients were followed for the duration of mechanical ventilation. Twenty patients diagnosed with iron deficiency anemia in the outpatient setting were enrolled as a control population. Control patients had baseline complete blood count and iron panel recorded by primary care physicians. EPO levels were measured at the time of enrollment in conjunction with complete blood count. RESULTS The mean EPO level for the control population was 60.9 mU/ml. The mean EPO level in the mechanically ventilated patient group was 28.7 mU/ml, which was significantly less than in the control group (P = 0.035). The mean hemoglobin value was not significantly different between groups (10.6 g/dl in mechanically ventilated patients versus 10.2 g/dl in control patients; P > 0.05). CONCLUSIONS Mechanically ventilated patients demonstrate a blunted EPO response to anemia. Further study of therapies directed at treating anemia of critical illness and evaluating its potential impact on mechanical ventilation outcomes and mortality is warranted.