The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP1) is a leading malaria vaccine candidate but is unable to induce immunity in all monkeys or all strains of mice. The mechanism of immunity is unclear, although data show that cell-mediated immunity plays a critical role following immunization with the larger mature MSP1 protein. We optimized a vaccine protocol using the MSP1(19) fragment of Plasmodium yoelii expressed in Saccharomyces cerevisiae, such that following exposure of mice to parasites, they remained undetectable in peripheral blood, whereas control animals all died at very high parasitemia within 10 days. We then depleted the vaccinated mice of >99% of CD4+ T cells by anti-CD4 mAb treatment and could show that infections in most animals remained subpatent following challenge. Furthermore, mice in which the gene for the mu-chain of Ig had been disrupted could not be immunized with MSP1(19). Immunity in normal mice did not depend on the presence of an intact spleen nor production of nitric oxide, persisting unabated when >70% of splenic macrophages were depleted. Thus, while effector CD4+ T cells may contribute to immunity, neither they nor factors associated with a Th1-type cell mediated immune response appeared to play the major role in MSP1(19)-induced protection in normal mice. Furthermore, T cells were not sufficient for immunity in mice lacking B cells. In normal mice, protection correlated with a very high titer of MSP1(19)-specific Abs (>6,400,000), predominantly G1 and G2b, which may function by merozoite neutralization.