Although there is good evidence that immunity to the blood stages of malaria parasites can be mediated by different effector components of the adaptive immune system, target antigens for a principal component, effector CD4 ⁺ T cells, have never been defined. We generated CD4 ⁺ T cell lines to fractions of native antigens from the blood stages of the rodent parasite, Plasmodium yoelii , and identified fraction-specific T cells that had a Th1 phenotype (producing IL-2, IFN-γ, and tumor necrosis factor-α, but not IL-4, after antigenic stimulation). These T cells could inhibit parasite growth in recipient severe combined immunodeficient mice. N-terminal sequencing of the fraction showed identity with hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT). Recombinant HGXPRT from the human malaria parasite, Plasmodium falciparum , activated the T cells in vitro , and immunization of normal mice with recombinant HGXPRT reduced parasite growth rates in all mice after challenge.