Survival characteristics, after transfusion, of erythrocytes from patients with homozygous sickle-cell disease were studied in rats. The study was made possible by previous injection of the animals with ethyl plamitate, which depressed reticuloendothelial system function, and with a factor in cobra venom that inactivated complement. This treatment prevented the rapid phagocytosis and intravascular hemolysis of donor erythrocytes that usually follow a heterologous transfusion. Both immediate after transfusion recovery and survival of ⁵¹Cr-labeled sickle erythrocytes were decreased in comparison to the values obtained for control erythrocytes from individuals without sickle-cell anemia. Survival of sickle erythrocytes was improved during exposure of the animals to 100% O₂. Hypoxia (7-10% O₂) resulted in the abrupt removal of 35-60% of sickle erythrocytes from the rats' circulation. Variations in oxygen tension did not affect survival of control erythrocytes. The usefulness of this convenient animal model for the study of sickle-cell anemia is suggested by the similarities between our results and the behavior of sickle erythrocytes in humans. The system may also be suitable for studying a wide variety of other human erythrocyte disorders.