The importance of the host gammadelta T cell response to microbial pathogens is not yet fully understood. We report that inbred mice infected with T. gondii developed a gammadelta T cell proliferative response to parasite Ag. Mice depleted of either the alphabeta or gammadelta TCR were found to be significantly more susceptible to infection than the parent mouse strain. Proliferation of gammadelta T cells was observed in mice deficient in the TCR-alphabeta in response to UV-irradiated parasites. These T cells lyse parasite-infected syngenic macrophages. Adoptive transfer of these gammadelta T cells into beta2 microglobulin-deficient mice that have been depleted of both CD4+ and NK cells prolongs survival against acute parasite challenge when compared with nontransferred controls. The gammadelta T cells isolated from infected alpha -/- mice express a 10-fold increase in mRNA and produce high titers of IFN-gamma. These data suggest that gammadelta T cells may play an important role in the early host response to infection with T. gondii.