Production of parasite-specific antibodies is an important component of immunity to blood stage malaria infection, as shown by several previous studies in rodent models. However, no study has addressed the induction of humoral immunity by different parasites in a genetically homogeneous host population. Here, levels of parasite-specific immunoglobulin isotypes were measured during primary infections of Plasmodium chabaudi and of Plasmodium yoelii in inbred NIH mice inoculated with cloned lines of either avirulent or virulent erythrocytic parasites. Non-lethal infections were characterized by early and late significant upregulation of IgG2a and IgG1, respectively. In contrast, for lethal infections, a slower, reduced IgG2a response correlated with a rapidly fatal outcome prior to any significant synthesis of IgG1. It is proposed that the sequential upregulated synthesis of parasite-specific IgG2a (cytophilic) and IgG1 (non-cytophilic) is associated with protective immunity to blood stage malaria infections in mice. This may provide an immunological framework for examining humoral immunity to malaria in humans.