Infection with Plasmodium berghei is lethal to mice, causing high levels of parasitemia, severe anemia, and death. However, when mice are treated with antimalarial drugs during acute infection, they have enhanced immunity to subsequent infections. With this infection and cure model of immunity, we systematically examined the basis of adaptive immunity to infection using immunodeficient mice. In order to induce adaptive immunity, mice were infected with blood-stage parasites. When the mice developed 2 to 3% parasitemia, they were treated with chloroquine to cure the infection. These convalescent mice were then challenged with homologous blood-stage parasites. Immunized wild-type mice were able to control the level of infection. In contrast, mice lacking mature B cells and T cells were unable to control a challenge infection, indicating the critical role of lymphocytes in immunity to P. berghei. Furthermore, mice lacking secreted antibody were unable to control the level of parasitemia following a challenge infection. Our results indicate that secreted antibody is a requirement for immunity to P. berghei.