Morphologic and functional changes in the spleen of BALB/cByJ mice in the course of Plasmodium chabaudi adami malaria were assessed by light and electron microscopy, augmented by probes of polystyrene spheres and autoradiography of injected 3H-uridine-labeled T lymphocytes. The initial phase of the disease (precrisis) was characterized by increasing parasitemia accompanied by a marked increase in spleen size and by anemia. Erythropoiesis predominated, but there was also plasmacytopoiesis and monocyte-macrophage differentiation. The white pulp increased due to enlargement of lymphatic nodules, and in the periarterial lymphatic sheath, plasma cells invade the area around the central artery. A decrease in splenic uptake was demonstrated by light microscopic analysis of concentration and distribution of intravenously injected, spleen-cleared polystyrene spheres. Stromal cells showing signs of intense protein secretion and increased branching were present. Branches of these cells, barrier cells, appeared to seal off from the blood the locules of filtration beds, protecting splenic erythropoiesis from parasitization. Barrier cells are recently recognized fibroblastic contractile stromal cells that fuse to form complex branched variform barriers used for such diverse functions as controlling blood flow and blood cell delivery into the circulation, sealing off the hematopoietic/immunologic colonies and regulating their proliferation and differentration through paracrine secretion. Normally present in marrow and spleen in limited numbers, barrier cells are quickly mobilized in hematopoietic/ immunologic stess. They may well be part of a larger system that includes the myofibroblasts of wound healing and myoepithelial cells. The following phase, crisis, was characterized by a sharp decrease in parasitemia, increased splenic uptake, and amelioration of the anemia. Again, the filtration beds were opened to the blood. In the succeeding phase of postcrisis, the structure of the spleen approached normalcy. Analysis of autoradiographs showed T cells from normal or immunized mice distributing equally to red pulp and white pulp at 1 hr after injection of isolated radioactively labeled T cells, but they increased in white pulp over time. A higher percentage of immune cells was found in the white pulp of mice on day 16 of infection, suggesting a role for these cells in the development of crisis. Interleukin-I-treated mice developed higher levels of parasitemia and lower levels of splenic uptake.