Anemia occurs in virtually all critically ill patients receiving long-term mechanical ventilation and has been associated with increased mortality and poor outcomes. Allogeneic RBC transfusions are routinely administered to critically ill anemic patients, especially during lengthy stays in ICUs or in long-term acute care facilities. Although RBC transfusions are a physiologically rational approach to raising hemoglobin levels, they may increase the risk of complications and have been associated with higher mortality in critically ill patients. Treatment with epoetin alfa, an erythropoiesis-stimulating agent, as a means of reducing transfusion requirements has been studied in the critically ill and in patients receiving long-term mechanical ventilation. Promising results have been reported, including a potential survival benefit, although larger and more definitive studies are needed in order to establish whether raising hemoglobin levels affects clinical outcomes in patients receiving mechanical ventilation.