Endothelins are potent endothelium-derived mediators regulating vascular function. Pleotropic effects of endothelins include stimulation of nitric oxide (NO) synthase. NO has in turn been shown to protect erythrocytes against suicidal death or eryptosis, which is characterized by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. On the other hand, endothelins have been shown to activate erythrocytic Ca²⁺- sensitive K⁺ channels thus leading to cell shrinkage. The present study explored whether endothelin 1 influences eryptosis. Energy depletion (removal of glucose) increased cytosolic Ca²⁺ activity, decreased cell volume and increased PS exposure as determined in FACS analysis. Endothelin 1 (500 nM) or the endothelin B (ETB) receptor agonist sarafotoxin (10 nM) significantly blunted the stimulating effect of glucose depletion on eryptosis. Mice deficient in ETB receptor (ETB^-/-) had significantly less erythrocytes than their wild type littermates (ETB^+/+). Moreover, annexin V-binding of erythrocytes taken from ETB^-/- compared to ETB^+/+ mice was enhanced. ETB^-/- were significantly more susceptible to the eryptotic effect of oxidative stress than ETB^+/+ erythrocytes. The observations disclose stimulation of the erythrocytic ETB receptor as a novel regulator of erythrocte survival in vitro and in vivo.