Varying doses of 5-azacytidine (5-aza) were given to four sickle cell individuals for 500, 200, 100, and 30 days. The percentage of fetal hemoglobin (HbF) containing reticulocytes (F reticulocytes) increased two- to five-fold within five days of 5-aza therapy in all patients, with a two- to three-fold rapid response (less than 48 hours after initial dose) in three patients. Reticulocyte suppression was not observed prior to, during, or after therapy in those patients who responded within 48 hours. Subcutaneous 5-aza was given in 35-day courses consisting of every day, every other day, or three consecutive days a week. No marrow toxicity was observed on any of the regimens. For three patients, the highest average F reticulocyte level was observed on the three consecutive day a week regimen. Oral 5-aza, given with tetrahydrouridine, produced comparable F reticulocyte response. In the two patients treated for more than 100 days, Hb levels increased to 11 to 12 and 9 g/dL, MCV and MCH increased by 25%, and lysate HbF levels peaked at 12% and 20%. Fetal erythroid characteristics (i- antigen, galactokinase activity, and G gamma/A gamma ratios) did not correlate with maximal HbF production. The frequency of vasoocclusive crises appeared to decrease in both patients followed for more than 100 days.