An important role in the intra- and intercellular communication depends on the controlled modulation of the intracellular Ca²⁺ concentration. Although this is well established for excitable and non-excitable cells, its putative role in the physiology of red blood cells is still unclear. Using fluorescence imaging and the patch-clamp technique on fresh human erythrocytes, we provide evidence that at physiological concentrations (10^-10 M) prostaglandin E₂ (PGE₂) activates Ca²⁺ rises mediated by Ca²⁺ influx through a nonselective cation-channel in human red blood cells. The extent of Ca²⁺ increase varied between cells with a total of 45% of the cells responding. It is well known that Ca²⁺ increases elicited the Ca²⁺-activated potassium channel (Gardos channel) in the red cell membrane. Previously, it was shown that the Gardos channel activation results in K⁺ efflux and shrinkage of the cells. Furthermore, intracellular Ca²⁺ rise in erythrocytes activates the lipid scramblase in the plasma membrane. Therefore, we conclude that the PGE₂ responses of red blood cells described here reveal a direct and active participation of erythrocytes in blood clot formation. PGE₂ can be produced by erythrocytes themselves. Therefore, the mechanism explained above may contribute to thrombus formation in coronary and cerebral arteries. Hence, it could be a cellular mechanism participating in such life threatening diseases like cardiac infarction and stroke.