Plasmodium chabaudi infection of mice provides an excellent model for examining acquired immunity to the blood-borne stage of malaria infection. CD4+ T-cell receptor (TCR) αβ-bearing T lymphocytes play a critical role in mediating protection, ascribed to both T helper (Th) 1 and Th2 subsets. One factor that may influence the Th1/Th2 cell balance is infective dose. In this study, we found that the size of the infective dose of P. chabaudi, and thus the level of antigen presented to the immune system, correlated with the balance of responder CD4+ T-cell phenotypes. Increasing the infective dose in a resistant mouse strain enhanced the Th1 cytokine (interferon-γ; IFN-γ) response and reduced the Th2 cytokine (interleukin-4; IL-4) response. In contrast, increasing the infective dose in a susceptible mouse strain led to a prominent and accelerated up-regulation of IL-4 production. These data show that the dose of antigen can significantly affect the balance between Th1- and Th2-mediated immune functions during infection of the mammalian host with blood-stage malaria parasites. This demonstration that parasite numbers may modulate CD4+ T-cell regulation has novel implications for the successful implementation of antimalarial vaccination and chemotherapeutic strategies.