Specific T-cell immunity to Listeria monocytogenes is thought to occur through the action of lymphokines which activate phagocytes to ingest and kill microorganisms. Interferon gamma (IFN-gamma) has been shown to be an effective mediator of this type of macrophage activation in vivo and in vitro. The monoclonal antibody H22.1 efficiently neutralizes endogenous IFN-gamma, exacerbates disease in a mouse model of L. monocytogenes infection, and inhibits the in vivo protective activity of a Listeria antigen-specific CD4 T-cell line. In contrast, in vivo protection by Listeria-immune CD8 T cells is not inhibited by the neutralizing anti-IFN-gamma monoclonal antibody. These results suggest that CD8 T cells can protect against an intracellular pathogen in an IFN-gamma-independent manner.