Vaccinia virus (VV) is a cytopathic virus that in normal mice exhibits only low virulence. However, when mice were treated throughout the course of the infection with mAb to IFN-gamma, the virus was lethal. The inability of these mice to clear the infection was not due to inhibition of effector T cell development since equally high numbers of cytotoxic T cells were generated in mAb- or control-treated mice. Instead, the data presented show that the defect was at the level of effector T cell activity. When immune CD8+ T cells were transferred to virus-infected recipients the infection was readily cleared. In contrast, effector cell function was totally blocked in mAb-treated recipients. We have considered these findings in view of our earlier observations that T cell deficient mice were able to resolve an otherwise lethal vv infection if infected with recombinant vv that encoded the genes for IL-2 or IFN-gamma. We propose a unifying concept such that antiviral T cells, which recognize infected cells in the context of class I MHC molecules, act to focus antiviral cytokines at the site of virus infection.