Patients with sickle cell disease are especially vulnerable to potential harms from unnecessary red blood cell transfusion. In particular, they experience an increased risk of alloimmunization to minor blood group antigens and a high risk of iron overload from repeated transfusions. Patients with the most severe genotypes of sickle cell disease with baseline hemoglobin values in the 7 to 10 g/dL range can usually tolerate further temporary reductions in Hb without developing symptoms of anemia. Many patients with sickle cell disease receive intravenous fluids to improve hydration when hospitalized for management of pain crisis, which may contribute to a decrease in hemoglobin by 1 to 2 g/dL. Routine administration of red blood cells in this setting should be avoided. Moreover, there is no evidence that transfusion reduces pain due to vaso-occlusive crises. For a discussion of when transfusion is indicated in sickle cell disease, readers are referred to recent evidence-based guidelines from the National Heart, Lung, and Blood Institute (see references).