γδ T cells are a diverse population of T cells that are widely distributed and are a common feature of pathogen-induced immune responses. It is not clear, however, whether different populations of γδ T cells have specific functions, and what factors determine the functional properties of individual populations. A murine model of peroral Toxoplasma gondii infection was used to determine the contribution Vγ1+ intestinal intraepithelial lymphocytes (IELs) vs systemic Vγ1+ T cells make to the acute and chronic stages of the host immune response, and whether the macrophage cytocidal activity of Vγ1+ T cells described in bacterial infections is seen in other, unrelated infectious disease models. In response to oral infection with virulent type 1 or avirulent type II strains of T. gondii, TCR-δ−/− mice rapidly developed severe ileitis. In contrast, in mice deficient in Vγ1+ T cells and IELs and wild-type mice, inflammation was delayed in onset and less severe. The protective effect of (Vγ1−) IELs to Toxoplasma infection was unrelated to their cytolytic and cytokine (Th1)-producing capabilities. Systemic Vγ1+ T cells were shown to play an essential role in limiting parasite growth and inflammation in peripheral tissues and, in particular, in the CNS, that was associated with their ability to efficiently kill parasite-elicited and infected macrophages. These findings suggest that macrophage cytocidal activity of Vγ1+ T cells may be a universal feature of pathogen-induced immune responses and that microenvironmental factors influence the involvement and function of γδ T cells in the host response to infection.