Mice experimentally infected with Plasmodium berghei NK65 were immunized with sheep red blood cells (SRBC) or polyvinylpyrrolidone (PVP), and the numbers of hemolytic plaque forming cells (PFC) produced in the spleen were measured. The antibody response showed two distinct phases. In the initial period of infection (Days 0–3), the PFC response to SRBC, a thymus-dependent antigen, was depressed, whereas the PFC response to PVP, a thymus-independent antigen, was normal. The PFC response to PVP was not depressed in infected athymic nude (nu/nu) mice, indicating that B cell function was not impaired at this stage of infection. Furthermore, spleen cells from malarial donor mice gave the same PFC response to SRBC when transferred to X-irradiated recipients, showing that neither B nor T cells are damaged at this stage. The suppressed immune response to SRBC was therefore attributed to dysfunction of the antigen-handling macrophages. When infection proceeded further (Days 5–7), the PFC response to SRBC was greatly depressed not only in the spleen but also in the popliteal lymph nodes, which had not shown suppressed responses in the earlier phase of infection. The response of spleen cells to PVP was also depressed at this time. The participation of suppressor cells in this immunosuppression was discounted, since spleen cells from malarial mice failed to suppress cells from normal animals when both types of cell were transferred simultaneously to X-irradiated recipients.