The rare McLeod blood group phenotype is characterized by weak Kell antigens, lack of the common Kx antigen, and acanthocytic morphology. Previous studies that did not detect membrane or cytoskeletal protein abnormalities suggested a lipid disturbance. In normal red cells, dimyristoyl phosphatidylserine (DMPS) is transported across the membrane by an enzymatic process and accumulates in the inner leaflet of the membrane bilayer causing discocyte to stomatocyte shape changes. Scanning electron microscopy of McLeod red cells shows a mixture comprised of 15% discocytes, 51% with irregular surfaces, and 34% acanthocytes. On incubation with various concentrations of DMPS at 37 degrees C for periods up to two hours, McLeod red cells transported DMPS across the membrane and caused irregularly shaped and acanthocytic McLeod red cells to attain normal discocyte shape and later to become stomatocytes. Chlorpromazine, which at 0 degrees C preferentially partitions into the inner monolayer of the membrane, had a similar effect on the shape of McLeod red cells. This suggests that in McLeod cells acanthocytosis is due to a lack of lipid in the inner leaflet of the membrane bilayer but that the imbalance is not caused by defective transport of phosphatidylserine across the membrane.