Infection with malaria parasites frequently induces total immune suppression, which makes it difficult for the host to maintain long-lasting immunity. Here we show that depletion of CD4(+)CD25(+) regulatory T cells (T(reg)) protects mice from death when infected with a lethal strain of Plasmodium yoelii, and that this protection is associated with an increased T-cell responsiveness against parasite-derived antigens. These results suggest that activation of T(reg) cells contributes to immune suppression during malaria infection, and helps malaria parasites to escape from host immune responses.