The in vivo survival of hereditary spherocytes has been investigated with the (51)Cr red cell survival technique. Spherocytes invariably showed a shorter survival in a normal recipient than in the donor's own circulation. Moreover transfusion of spherocytes from a mother to her son, both with hereditary spherocytosis, showed that "foreign" spherocytes have a shorter survival than the "self" spherocytes of the recipient. These findings are attributed to splenic reticuloendothelial blockade, specific towards hereditary spherocytes in the patient's own circulation. There was no correlation between the Na(+) influx and the hemolytic tendency of hereditary spherocytes when the latter was measured by the survival t(1/2) in compatible normal recipients. However osmotic fragility influenced cell survival since cells with high fragility were rapidly sequestered in the normal spleen. It is suggested that both cell shape and a selective reticuloendothelial blockade in the spleen are important factors in determining the severity of hemolysis in the individual patient.