Activation of erythrocyte Ca2+ permeable cation channels leads to eryptosis, a suicidal death characterized by decrease of cell volume, cell membrane blebbing, and phosphatidylserine (PS) exposure at the cell surface. The present study investigates whether eryptosis is affected in genetically modified mice overexpressing erythropoietin (tgEPO). RBC number, packed cell volume, and hemoglobin concentration were higher but forward scatter reflecting cell volume smaller in peripheral blood from tgEPO mice than from WT mice. The percentage of PS exposure and cytosolic Ca2+ activity were larger in tgEPO- than in WT- RBCs. tgEPO-RBCs were more resistant to osmotic lysis than WT-RBCs. Cl- removal and exposure to the Ca2+ ionophore ionomycin (1 mM) increased PS exposure and decreased forward scatter, effects larger in tgEPO- than in WT-RBCs. Increase of extracellular K+ to 125 mM abrogated the difference between tgEPO- and WT-RBCs in PS exposure. The K+ ionophore valinomycin (10 nM) triggered eryptosis of both tgEPO- and WT- RBCs and decreased the differences between the genotypes. EPO led to a slight decrease of PS exposure and increase of forward scatter of tgEPO-RBCs but did not yield values similar to WT- RBCs. In conclusion, RBCs from tgEPO mice are sensitized to triggers of eryptosis but more resistant to osmotic lysis, properties at least partially due to enhanced Ca2+ entry and increased K+ channel activity.