Morphological and functional changes in the spleen of BALB/cByJ mice in the course of P. c. adami malaria were assessed by light and electron microscopy, augmented by probes of polystyrene spheres and autoradiography of injected H-uridine-labeled T lymphocytes. The initial phase of the disease (precrisis) is characterized by rising parasitemia accompanied by marked increase in spleen size and by anemia. Erythropoiesis predominates, but there is also plasmacytopoiesis and monocyte-macrophage differentiation. The white pulp increases due to enlargement of lymphatic nodules, and, in the PALS, plasma cells invade the area around the central artery. A decrease in splenic uptake is demonstrated by analysis of sphere concentration. Stromal cells showing signs of intense protein secretion and increased branching are present. Branches of these cells, barrier cells, appear to seal off from the blood the locules of filtration beds, protecting splenic erythropoiesis from parasite. The following phase, crisis, is characterized by a sharp decline in parasitemia, increased splenic uptake, and amelioration of the anemia. Again the filtration beds are opened to the blood. In the postcrisis the structure of the spleen is approached. Analysis of autoradiographs shows T cells from normal or immunized mice distributing equally to red pulp and white pulp at 1 hr, but they increase in white pulp overtime. A higher percentage of immunized cells is found in the white pulp of mice on day 16 of infection, suggesting a role for these cells in the development of crisis. Interleukin 1-treated mice developed higher levels of parasitemia and lower levels of splenic uptake.