Exposure of erythrocytes to osmotic shock, oxidative stress and energy depletion activates Cl--sensitive and Ca2+-permeable cation channels. Subsequent Ca2+ entry triggers eryptosis, characterized by erythrocyte shrinkage and phosphatidylserine exposure. Erythro-cytes exposing phosphatidylserine are recognized, bound, engulfed and degraded by macrophages. Eryptosis thus fosters clearance of affected erythrocytes from circulating blood. In this study, we investigated whether iron deficiency leads to anemia in part by decreasing erythrocyte life span. For this, erythrocytes from mice on control diet were compared to erythrocytes from mice exposed 10 weeks to iron deficient diet. Iron deficiency significantly (P<0.001) enhanced erythrocyte annexin-V binding (from 2.4% to 3.7%), decreased forward scatter (from 544 to 393) and increased cytosolic Ca2+ concentration. 45Ca2+ flux measurements and patch clamp experiments revealed enhanced Ca2+ uptake (by 2.3-fold), and cation channel activity. Furthermore, the half-life of fluorescence-labelled, iron-deficient erythrocytes was significantly reduced as compared with control erythrocytes (from 23 to 15 days). Thus, the experiments reveal a novel mechanism triggered by iron deficiency which presumably contributes to accelerated clearance of erythrocytes in iron deficiency anemia.