The mitogen- and stress-activated protein kinase MSK1 participates in the signal transduction critical in the regulation of nucleated cell survival and apoptosis. Erythrocytes may similarly undergo suicidal erythrocyte death or eryptosis, characterised by cell shrinkage and cell membrane scrambling leading to and phosphatidylserine exposure at the erythrocyte surface. To elucidate whether MSK1 influences eryptosis, erythrocytes were isolated from mice lacking functional MSK1 (msk1^-/-) and their corresponding wild type mice (msk1^+/+). MSK1 expression in erythrocytes was estimated by western blot. Phosphatidylserine exposure (Annexin-binding) and cell volume (forward scatter) were determined using FACS. Annexin-binding was similar in untreated msk1^-/- and msk1^+/+erythrocytes, but was increased by hyperosmotic shock (+550mM sucrose) or energy depletion (removal of glucose for 12 hours) to significantly higher levels in msk1^-/-erythrocytes than in msk1^+/+erythrocytes. Similarly, forward scatter was similar in untreated msk1^-/- and msk1^+/+erythrocytes, but was decreased by hyperosmotic shock or energy depletion to significantly lower levels in msk1^-/- erythrocytes than in msk1^+/+erythrocytes. Resistance to decreasing extracellular osmolarity was lower in msk1^-/-erythrocytes than in msk1^+/+erythrocytes. Red blood cell count, hematocrit, blood hemoglobin concentration, mean erythrocyte volume and mean erythrocyte hemoglobin content were not significantly different between msk1^-/- and msk1^+/+mice. Reticulocyte numbers were, however, significantly increased in msk1^-/-mice, pointing to enhanced erythrocyte turnover. The clearance of CFSE-labelled erythrocytes and the appearance of labeled phosphatidylserine exposing erythrocytes in the spleen were significantly faster in msk1^-/-mice. The observations point to accelerated eryptosis in msk1^-/-erythrocytes, which contribute to or even accounts for the enhanced erythrocyte turnover, anemia and splenomegaly in those mice.