Abstract Four distinct erythrocyte membrane sialoglycoproteins (SGPs) denoted alpha, beta, gamma, and delta have been described, but their functions have not yet been defined. Recent evidence suggests that several of these SGPs associate with membrane skeletal proteins. Because the membrane skeletal protein network plays an important role in regulating the membrane material properties of deformability and mechanical stability, we wanted to determine whether the SGPs, through their interaction with the membrane skeleton, can modulate these membrane properties. We measured membrane mechanical stability and membrane deformability of erythrocytes that were deficient in either alpha, or delta or beta and gamma SGPs. Only erythrocytes deficient in beta and gamma SGP had altered membrane properties, as evidenced by marked decreases in both membrane mechanical stability (50% of normal) and membrane deformability (40% of normal). Erythrocytes deficient in either alpha or delta SGP had normal deformability and stability. Based on these data, we suggest that an interaction of beta and/or gamma SGP with the membrane skeleton plays a functionally important role in regulating normal erythrocyte membrane properties.