Poikilocytosis of red blood cells (RBCs) was observed to be associated with anemia in rats given subcutaneous injections of cadmium (Cd). Phase-contrast light and scanning electron microscopic examinations revealed that acanthocytes appeared in the early stages of administration, and that the number of RBC fragments increased later. Ultrastructural analysis of RBC ghosts by negative staining demonstrated that the normal lattice structure of the membrane skeleton was abolished. The osmotic fragility curve of the Cd-exposed RBCs disclosed that most of the cells were less fragile than control RBCs. These data indicate that the RBC membrane skeleton is initially altered by Cd-exposure, followed by deformation of the cell, thus promoting intrasplenic hemolysis, and resulting in anemia.