Glycophorin A is the major sialoglycoprotein of the human erythrocyte membrane. Structural studies indicate that this molecule is made up of 3 domains composed of 2 hydrophilic segments which are separated by a region of 22 nonpolar amino acids. The N-terminal half of the molecule contains all the carbohydrate associated with this protein. Glycophorin A forms high-molecular-weight complexes which can be dissociated only under certain conditions. The site of subunit interaction is located within the hydrophobic segment, which serves both to mediate protein-protein and protein-lipid interactions within the bilayer membrane. Glycophorin A spans the membrane presumably as a dimeric complex with the carboxyterminal ends extending into the cytoplasm of the red cell. The transmembrane nature of the polypeptide chains finds strong support from the use of specific antibody-ferritin conjugates applied to thin sections of fixed and frozen intact cells. Preliminary information on the analysis of human red cell variants which may lack some or all of the sialoglycopeptides are consistent with the presence in normal cells of a second sialoglycoprotein, provisionally labeled glycophorin B.