Erythropoietin is being used more widely in the management of sickle cell disease (SCD, inclusive of homozygous sickle beta, SS, and compound heterozygous sickle beta thalassemia, Sbeta0 thal), often in conjunction with hydroxyurea (HU). Herein, we summarize the published experience with erythropoietin use in SCD, in 39 patients (SS, n = 30; Sb0 thal, n = 9) who were treated between 1990 and 1996; and in 13 patients with sickle syndromes (SS, n = 12, compound heterozygous SC disease, n = 1) who were treated with erythropoietin or darbepoietin at the National Institutes of Health (NIH) since 2002. The dose range of erythropoietin for SCD in the published series, at a median of > 200 U/Kg/dose, is higher than that used in end-stage renal disease. The median duration of erythropoietin therapy was > or =3 months, with minimal reported side-effects. At the NIH, the median age of sickle syndrome patients who received erythropoietin or darbepoietin (both referred to as EPO in the NIH series) was 51 (24 to 70) years; 12/13 patients had sickle-associated pulmonary hypertension. Eleven out of the 13 patients were treated with both HU and EPO for > 4 months (median of 11 months on EPO) without complication. Of the 13 patients, five (all SS) with pulmonary hypertension were given EPO for reticulocytopenia (< 100,000/mL) on HU; 5/13 patients (all SS), with pulmonary hypertension, were given EPO and HU concurrently, in the light of an estimated glomerular filtration rate of < 80 mL/minute. Three of the 13 patients (2 SS, 1 SC) were treated with EPO for miscellaneous reasons. Hematologic responses, detailed herein, suggest that EPO therapy may allow more aggressive HU dosing in high-risk SCD patients and in the setting of mild renal insufficiency, common to the aging sickle cell population. Furthermore EPO appears to be safe in SCD, particularly when used in conjunction with HU. We outline our current therapeutic strategy for EPO use in SCD.