To determine whether diminished activity of the Ca2+ extrusion pump could account for the high levels of red blood cell (RBC) Ca2+ in sickle cell anemia (SS), calmodulin-sensitive Ca2+ ATPase activity in normal and SS RBC was measured. Hemolysates prepared with saponin were compared, since such preparations expressed maximum ATPase activities, exceeding isolated membranes or reconstituted systems of membranes plus cytosol. SS RBC hemolysates had greater Ca2+ ATPase activity than normal hemolysates; they exhibited higher Mg2+, Na+ and K+ ATPase activities as well. Assays on density (age) fractions of SS and normal red cells demonstrated that all ATPase activities were highest in low density (young) cells, and activities in SS red cells exceeded those in normals in all fractions studied. When studied under conditions that maximize enzyme activity, Ca2+ ATPase activity like Mg2+, Na+ and K+ ATPase is actually increased in SS RBC, probably due to the young red cell population present. The elevated Ca2+ levels in these cells are more likely due to an increased Ca2+ leak or abnormal Ca binding than defective extrusion by the ATPase pump.