Amyloid peptides induce apoptosis in a wide variety of cells. Erythrocytes may similarly undergo suicidal death or eryptosis, characterized by scrambling of the cell membrane with subsequent exposure of phosphatidylserine (PS) at the cell surface. Eryptosis is triggered by increase of cytosolic Ca2+ activity and by activation of acid sphingomyelinase with subsequent formation of ceramide. Triggers of eryptosis include energy depletion and isosmotic cell shrinkage (Cl- depletion). The present study explored whether amyloid peptide Ab1-42 could trigger eryptosis and to possibly identify underlying mechanisms. Erythrocytes from healthy volunteers were exposed to amyloid peptide Ab1-42 and PS-exposure (Annexin V binding), cell volume (forward scatter), cytosolic Ca2+ activity (Fluo3 fluorescence) and ceramide formation (anti-ceramide antibody) were determined by FACS analysis. Exposure of erythrocytes to the amyloid peptide Ab1-42 (0.5 mM) for 24 hours significantly triggered Annexin V binding and decreased erythrocyte forward scatter. The effect was paralleled by formation of ceramide but not by significant increase of cytosolic Ca2+ activity. Ab1-42 further significantly enhanced the eryptosis following Cl- depletion but not of glucose depletion for 24 hours. The present observations disclose a novel action of Ab1-42 , which may well contribute to the pathophysiological effects of amyloid peptides, such as vascular complications in Alzheimer's disease.