Adenomatous polyposis coli (APC) is a tumor suppressor gene inactivated in familial adenomatous polyposis and sporadic colorectal cancer. In contrast to their wild type littermates (apc^+/+), mice carrying a loss-of-function mutation in the apc gene (apc^Min/+) spontaneously develop gastrointestinal tumors. Incidently, we observed anemia and splenomegaly in apc^Min/+ mice, pointing to enhanced sequestration of circulating erythrocytes. The present study explored the possible involvement of eryptosis, the suicidal death of erythrocytes which is stimulated by an increase in the cytosolic Ca²⁺ concentration and characterized by cell shrinkage and phosphatidylserine expsoure at the erythrocyte surface. The percentage of reticulocytes was dramatically higher in apc^Min/+ (50.6 1.9%) than in apc^+/+ (3.3 0.2%) erythrocytes. Following a 24 hour incubation in physiological solution, the percentage of annexin V-binding erythrocytes was again significantly higher in apc^Min/+ (23.8 4.8%) than in apc^+/+ (3.1 0.3%) erythrocytes. The enhanced exposure of phosphatidylserine at the surface of apc^Min/+ erythrocytes was paralleled by cell shrinkage and a significantly increased Ca²⁺ concentration of apc^Min/+ compared to apc^+/+ erythrocytes. In conclusion, this study identifies a possible role of APC as a regulator of the survival of mature erythrocytes.