Eryptosis, the suicidal death of erythrocytes, is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by increase in cytosolic Ca²⁺ concentration. Ca²⁺ entry may be triggered by endogenous prostaglandin E2, which partially accounts for the stimulation of eryptosis following osmotic shock. The eryptosis following energy depletion is, however, not prevented by cycloxygenase inhibition. The present study explored the involvement of leukotrienes. As a result, erythrocytes expressed the leukotriene receptor CysLT1. Glucose depletion (24 h) significantly increased the formation of the cysteinyl-leukotrienes LTC4/D4/E4. LTC4 (10 nM) increased Ca²⁺ entry, decreased forward scatter and stimulated annexin V-binding. Glucose depletion similarly increased annexin V-binding, an effect significantly blunted in the presence of the leukotriene receptor antagonist cinalukast (1 mM) or the 5-lipoxygenase inhibitor BWB70C (1 mM). In conclusion, upon energy depletion erythrocytes form leukotrienes, which in turn activate cation channels, leading to Ca²⁺ entry, cell shrinkage and cell membrane scrambling. CysLTs thus participate in the signaling of eryptosis during energy depletion.