The energy sensing AMP-activated protein kinase (AMPK) has previously been shown to counteract eryptosis, the suicidal death of erythrocytes characterized by shrinkage and phosphatidylserine exposure at the cell surface. Eryptosis is triggered by energy depletion, an effect at least partially due to increase of cytosolic Ca²⁺ activity. The present study explored, whether energy depletion and increase of cytosolic Ca²⁺ activity trigger phosphatidylserine-sensitive adhesion of erythrocytes to endothelial cells, and whether this effect is modified by AMPK. Human erythrocytes or erythrocytes from AMPKa1-deficient mice (ampk^-/-) and wild type littermates (ampk^+/+) have been exposed to glucose depletion for 48 hours or treated with Ca²⁺ ionophore ionomycin (1mM for 30min) in absence or presence of AMPK activator AICAR (1mM) or AMPK inhibitor compound C (20mM). Erythrocyte phosphatidylserine exposure was estimated from annexin binding in FACS-analysis, erythrocyte adhesion from attachment to human vascular endothelial cells (HUVEC) in a flow chamber. As a result, eryptosis and adhesion to HUVEC was minimal in energy replete erythrocytes and was not significantly modified by AICAR or compound C. Glucose depletion and ionomycin markedly increased eryptosis and adhesion to HUVEC, effects significantly blunted by AICAR and significantly augmented by compound C. Eryptosis and adhesion were similar in ampk^-/-erythrocytes and ampk^+/+erythrocytes under control conditions but were significantly higher in ampk^-/- erythrocytes than in ampk^+/+erythrocytes following glucose depletion or treatment with ionomycin. Adhesion was inhibited by coating of phosphatidylserine with annexin. The present observations disclose a crucial role of AMPK in the adhesion of erythrocytes to the vascular wall.