The underlying cause of anemia is one of the problems to be solved in malaria research. Many factors are involved in reducing the quantity of uninfected red blood cells (RBC) in addition to those infected RBC destroyed by malaria parasites. In the Plasmodium yoelii (P.y.)-mouse model, the amount of [51Cr]-labelled normal mouse RBC destroyed in peripheral blood as well as the quantity phagocytized by spleen cells during acute and chronic infection in vivo is reported in this paper. Our results show that compensatory enlargement of the spleen, which cleans up a large amount of the damaged uninfected RBC, may be the major cause of anemia in chronic malaria infection. In acute malaria infection destruction of uninfected RBC in peripheral circulation is higher than that in normal mice. Neither malaria antigen, mouse autoantibody nor immune complex was detected on the surface of normal RBC from infected mice using indirect immunofluorescence assay (IFA) or [3H]-isoleucine-labelled P.y. antigen (P.y.Ag) in vitro. This suggests that malaria immune complexes do not play an important part in RBC destruction in circulating blood. Since no obvious hemolysis was observed by mixing RBC with P.y. culture supernatant in vitro, it is possible that physical and chemical changes in uninfected RBC induced by malaria metabolites are the prerequisite for their destruction in circulating blood in vivo. Hemolysis occurs due to external stresses, such as those incurred when damaged RBC run into each other in the blood stream or when they change their shape to pass through capillaries.