To investigate the mechanism of pharmacologic stimulation of fetal hemoglobin in sickle-cell anemia (hemoglobin S disease), we treated two patients with homozygous disease with various doses of cytarabine (also known as Ara-C) or hydroxyurea and evaluated the effects of each treatment on F-reticulocyte production and on hemopoiesis. The treatments stimulated F-cell production in a dose-related fashion. Treatments that increased F-cell production also increased the patient's hematocrit and caused only minor, transient decreases in white cells. The main effect on erythropoiesis consisted of cytoreduction of the mature erythron (as assessed by measurements of reticulocytes) or a decrease in the compartment of erythroid progenitors (colony-forming units-erythroid and burst-forming units—erythroid). The reduction phase was followed by reticulocyte regeneration, during which most of the increase in the absolute numbers of F reticulocytes took place. Lower doses of cytarabine or hydroxyurea resulted in smaller waves of reticulocyte regeneration and lesser effects on F-reticulocyte production. These results suggest that the main cause of stimulation of fetal hemoglobin in patients with sickle-cell anemia treated with cell cycle—specific compounds is the erythroid regeneration triggered by the drug treatment. (N Engl J Med 1985; 313: 1571–5.)