Effect of intraerythrocyte Ca2+ elevation on human and rat erythrocyte membrane (Ca2+Mg2+)-ATPase along with that of incubation of the erythrocyte ghosts in their own hemolysates enriched With Ca2+ has been studied. While the membrane (Ca2+-Mg2+)-ATPase levels of Ca2+-loaded human erythrocytes showed an initial increase and subsequent decline, membranes incubated in their own hemolysate showed a consistent decrease in the enzyme activity. Calmodulin sensitivity was by the preparations in contrast to the earlier observations made with washed erythrocyte membranes. Similar changes in (Ca2+-Mg+)-ATPase activity but of greater magnitude were observed in response to Ca2+ in the calpain-rich rat erythrocytes. Considerable crosslinking and proteolysis was observed in case of human and rat erythrocytes exposed to high Ca2+ concentrations. The Ca2+-activable transglutaminase, however, did not play any role in the activation of the (Ca2+-Mg2+)-ATPase.