The appearance of phosphatidylserine, an aminophospholipid normally confined to the inner monolayer, at the outer leaflet of red cell membrane may have several pathophysiologic implications. This study examines erythrocyte phosphatidylserine exposure in chronic renal failure (CRF) patients on conservative treatment or on dialysis, to assess possible alterations to phospholipid asymmetry in a condition associated with a state of deranged red cell function. A significant increase in phosphatidylserine-expressing erythrocytes was found in undialyzed patients with CRF (2.32%) and patients on hemodialysis (3.06%) and on peritoneal dialysis (2.14%) compared with control subjects (0.68%). In undialyzed CRF patients, a strong correlation (r = 0.903) was found between the percentage of phosphatidylserine-expressing red cells and the serum creatinine concentration. The increased exposure of phosphatidylserine in uremic erythrocytes may be due to inhibition of phosphatidylserine transport from the outer to the inner leaflet of plasma membrane and may promote an increased erythrophagocytosis. In reconstitution experiments, normal erythrocytes showed an increase in phosphatidylserine-expressing cells when incubated in uremic plasma (3.2% after 2 h versus 1.1% at beginning of incubation), whereas phosphatidylserine-positive uremic erythrocytes decreased when resuspended in normal plasma (2.03% after 2 h and 1.65% after 8 h versus 2.9% at beginning of incubation). Preliminary characterization of the putative uremic compound(s) indicates a molecular weight between 10,000 and 20,000, as well as heat instability. These findings show an impairment of erythrocyte membrane phospholipid asymmetry in CRF patients, regardless of the dialysis treatment. Such abnormality seems related to the uremic state and could contribute to the red cell pathology present in CRF.