Eryptosis, a suicidal death of mature erythrocytes, is characterized by decrease of cell volume, cell membrane blebbing and breakdown of cell membrane asymmetry with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increased cytosolic Ca²⁺-activity which could result from activation of Ca²⁺-permeable cation channels. Ca²⁺ triggers phosphatidylserine exposure and activates Ca²⁺-sensitive K⁺-channels leading to cellular K⁺-loss and cell shrinkage. The cation channels and thus eryptosis are stimulated by Cl^--removal and inhibited by erythropoietin. The present experiments explored eryptosis in transgenic mice overexpressing erythropoietin (tg6). Erythrocytes were drawn from tg6 mice and their wild type littermates (WT). Phosphatidylserine exposure was estimated from annexin binding and cell volume from forward scatter in FACS analysis. The percentage of annexin binding was significantly larger and forward scatter significantly smaller in tg6 than in WT erythrocytes. Transgenic erythrocytes were significantly more resistant to osmotic lysis than WT erythrocytes. Cl^--removal and exposure to Ca²⁺-ionophore ionomycin (1 µM) increased annexin binding and decreased forward scatter, effects larger in tg6 than in WT erythrocytes. The K⁺-ionophore valinomycin (10 nM) triggered eryptosis in both tg6 and WT erythrocytes and abrogated differences between genotypes. An increase of extracellular K⁺-concentration to 125 mM blunted the difference between tg6 and WT erythrocytes. Fluo3-fluorescence reflecting cytosolic Ca²⁺-activity was larger in tg6 than in WT erythrocytes. In conclusion, circulating erythrocytes from tg6 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.