To investigate the role of cell-mediated immunity in the control of Mycobacterium avium infection, we studied the effects of targeted gene disruptions in components of the T lymphocyte-dependent, macrophage-mediated response on resistance of mice to this pathogen. Normal mice developed a chronic, asymptomatic infection, with rapid induction of mRNAs for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bacterial loads in gene knockout, scid, and wild-type mice were indistinguishable for the first 4 wk of infection. However, by 8 wk postinfection, scid mice as well as animals with a targeted disruption of the IFN-gamma gene showed enhanced bacterial growth compared with wild-type controls. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only developed comparable bacterial loads to wild-type animals, they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type controls. Thus, M. avium is clearly distinct from other intracellular pathogens (e.g., Leishmania monocytogenes, Toxoplasma gondii, and Mycobacterium tuberculosis) whose initial replication in the host is tightly controlled by Th1-dependent effector mechanisms. Instead, the major effect of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide appears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.