The management of severe anemia in patients who do not accept heterologous blood transfusion for religious reasons presents many different challenges both at the level of treatment strategy and ethics. Recently, new interventional treatment strategies have become available, including human and bovine hemoglobin substitutes and high-dose recombinant human erythropoietin. We present the successful management of two Jehovah's Witnesses patients with severe, life-threatening anemia caused by chronic renal failure and exacerbated by sepsis.