Serum which protects rats against Plasmodium berghei infections fails to sensitize parasitized erythrocytes in vitro for in vivo destruction. Further, the efflux of 86Rb from parasitized erythrocytes in the presence of complement is not accelerated. On administration to animals with preexisting malaria, it does, however, produce a relatively slow decline in parasitemia, a phenomenon interpreted in terms of the gradual production and/or release of reactive antigenic determinants associated with maturation of the parasites. Protective activity is elaborated in the serum of animals during the development of parasitemia, thus creating a situation in which there is apparently the coincident presence of antibody and its putative antigen in the circulation. Little absorption of protective activity by parasitized cells or parasites was observed in vitro. However, in vivo removal of the protective activity during an ongoing infection could be demonstrated. These observations favor the notion that protective antibody exerts its influence not on the bulk of the parasitized erythrocytes, but rather on some subpopulation thereof. The cumulative evidence of this and other studies suggests that the stage(s) involved are the schizonts and/or merozoites.