Sickling of reticulocytes and mature erythrocytes from patients with sickle cell disease was compared at venous and arterial oxygen tensions (PO2 = 30 and 90 mm Hg). Reticulocyte-rich fractions (d < 1.06) were partially deoxygenated in two ways after incubation at PO2 = 180 mm Hg: (1) PO2 of 30 mm Hg for 1 hour, and reoxygenation to 90 mm Hg for 2 hours and (2) PO2 of 90 mm Hg and kept for 2 hours. Percentages of sickled cells were always higher (3-5 times) in reticulocytes than in mature erythrocytes. Percentage of sickled reticulocytes measured at PO2 = 90 mm Hg after partial deoxygenation to PO2 = 30 mm Hg was 2 times higher than that obtained directly at PO2 = 90 mm Hg. In contrast, there was no difference in percentage of sickled cells in the mature erythrocyte population under the two experimental conditions. These results suggest that reticulocytes are more susceptible to sickling under venous oxygen tension and less likely than mature erythrocytes to resume discoidal shape even at arterial oxygen tension.