Erythrocytes from Cu deficient rats, which had normal plasma Zn but low plasma Cu (high Zn:Cu), were more stable to osmotic stress than those from controls. Erythrocytes from Zn deficient rats, which had low plasma Zn and high plasma Cu (low Zn:Cu), were more fragile than those from controls. Addition of Cu2+ and Zn2+ to normal red cells in vitro to provide a low Zn:Cu ratio increased hemolysis and peroxidation. In general, erythrocyte membranes were sensitive to the concentrations of extracellular Cu and Zn. The effects were inversely related, Zn exerting a stabilizing and Cu a labilizing effect. Ceruloplasmin levels increased in Zn deficiency, but RBC [red blood cell] superoxide dismutase (SOD) activity was unaffected. SOD activity may be useful as a clinical index of tissue Cu status.