Gamma interferon (IFN-gamma) is known to be a major mediator influencing host defense against Toxoplasma (T.) gondii. To evaluate lymphocyte populations involved in this cytokine-mediated early resistance to T. gondii, the effects of in vivo administration of monoclonal antibodies (MAbs) against T-cell subsets and anti-asialo GM1 antibody on the course of infection and IFN-gamma response were investigated in mice infected acutely with this parasitic protozoan. A single injection of anti-CD8 MAb on day -1 or day 4 severely exacerbated the infection, in accordance with a marked suppression of endogenous IFN-gamma production. Moreover, the administration of anti-IFN-gamma MAb on day 0 but not later than day 4 resulted in a total abrogation of resistance to T. gondii, suggesting that endogenous IFN-gamma produced during the first several days of infection is critical for the generation of antitoxoplasmal resistance in mice. In contrast, no significant increase in mortality was observed when injected with either anti-CD4 MAb or anti-asialo GM1 antibody on day -1, while these antibodies reduced significantly the ability of mice to produce IFN-gamma. Indeed, simultaneous depletion of CD4+ and CD8+ cells had no greater suppressive effect on host defense and endogenous IFN-gamma production than depletion of CD8+ cells alone. Together, these results suggest that CD8+ T cells play a central role for resolution of acute toxoplasmosis by participating in endogenous IFN-gamma production. The possible role of early produced IFN-gamma in the development of protective immune response to T. gondii is also discussed.