Cytokine and cytokine receptor gene knockout mice provide powerful experimental systems to characterize the functions of these molecules in resistance to infectious disease. Such mice may also provide unique models of immune deficiency to learn whether manipulation of the immune response can overcome the specific dysfunction. We demonstrate that resistance of IFN gamma gene knockout (GKO-/-) mice to the intracellular bacterium Listeria monocytogenes is severely impaired compared with wild-type mice. However, immunization of GKO-/- mice with an attenuated L. monocytogenes strain generates antigen-specific CD8 T cell responses that can transfer immunity to naive hosts. Furthermore, vaccinated GKO-/- mice themselves exhibit 20,000-fold increased resistance to challenge with virulent L. monocytogenes and this resistance appears to be CD8 T cell mediated. These studies demonstrate that vaccination-induced immunity can overcome the absence of a cytokine that is critical for resistance to acute infection.