The purpose of this study was to determine a possible correlation between the cell populations of the immune system in the spleen, and the failure of normal Balb/c mice to overcome a Plasmodium berghei infection. After primary infection, all splenic white cell populations increased in number. However, the ratios between the different cell populations changed markedly. Macrophages, which comprise 5-10% of normal white spleen cells, rose to 70-80?% during the lethal infection. Most of the macrophages lacked surface Ia antigens. A rise in macrophage precursors in the spleen was also observed. The lymphocyte population was characterized by a preferential increase of T-suppressor-cytotoxic (Tsc) cells resulting in an inversion of the Tsc/Thelper ratio. During chloroquine treatment, administered in order to cure infected mice, all splenic populations remained expanded but their quantitative proportions returned to normal. Secondary infection of cured mice did no cause an additional increase in the number of splenic white cells, nor did it affect the ratios between the various populations. It appears that normal quantitative relations between spleen cell populations is a hallmark of the host's capability to overcome infection with P. berghei. The failure of the immune system, as seen during a lethal infection, may be due to the preferential increase in immature, functionally defective macrophages and possibly T-suppressor lymphocytes. Alternatively, the changes in macrophages and T lymphocytes described could be a result of rather than the cause of the high parasitemia observed during P. berghei infection.