Perforin-mediated cytotoxic T cell killing has been suggested to be of importance in the control of noncytopathic virus infections, based on studies with lymphocytic choriomeningitis virus (LCMV). We examined the role of perforin in a mouse model of gammaherpesvirus infection using transgenic perforin-deficient mice. Previous work from this laboratory has shown that CD8 T cells are essential for the resolution of the acute lung infection and control of latently infected B cells in murine gammaherpesvirus 68 infection. The absence of perforin did not significantly affect the kinetics of either the lytic lung infection or the latent spleen infection. Lymphocytes from both perforin-deficient and control mice secreted comparable levels of IFN-γ, IL-10 and IL-6. In addition, lymphocytes from both strains had similar levels of CD3ε-dependent cytotoxic activity in the spleen, draining lymph nodes and bronchoalveolar lavage. These data indicate that the lack of perforin has little affect on the ability of mice to control an experimental gammaherpesvirus infection.