The consequences of Sickle Cell Disease (SCD), including ongoing hematopoietic stress and hemolysis, vascular damage and chronic therapies , such as blood transfusions and Hydroxyurea on hematopoietic stem and progenitor cell (HSPC) have not been characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients stratified by treatment and controls. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, and two to five-fold more CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a and by very high levels of expression of the CD49f antigen. These findings were present to varying degrees in all patients, whether or not they were naïve or on chronic therapy. HU treatment tended to normalizes many of these parameters. Chronic stress erythropoiesis, inflammation caused by SCD and hydroxyurea therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.