Immunoglobulin G was separated on cellulose phosphate column to afford four distinct protein fractions (CP-I, II, III and IV). 125I-labeled fractions CP-III and CP-IV were found to be capable of binding specifically to normal human erythrocytes. The effect of the four fractions on osmotic resistance of red blood cells (RBC) was studied. RBC were obtained from eight patients with hereditary spherocytosis (HS), from a single parent of two non-related patients, and from five normal donors. RBC fragility of normal and one parent were unaffected by any of the immunoglobulin fractions. In contrast, a small but significant decrease in osmotic resistance was observed when RBC from HS patients and the second parent were incubated with protein fractions CP-III and CP-IV.