Gamma interferon (IFN-γ) and T1-phenotype immune responses are important components of host defense against a variety of intracellular pathogens, including Legionella pneumophila. The benefit of intrapulmonary adenovirus-mediated IFN-γ gene therapy was investigated in a nonlethal murine model of experimental L. pneumophilapneumonia. Intratracheal (i.t.) administration of 10⁶ CFU of L. pneumophila induced the expression of T1 phenotype cytokines, such as IFN-γ and interleukin-12 (IL-12). Natural killer cells were identified as the major cellular source of IFN-γ. To determine if enhanced expression of IFN-γ in the lung could promote pulmonary clearance of L. pneumophila, we i.t. administered 5 × 10⁸ PFU of a recombinant adenovirus vector containing the murine IFN-γ cDNA (AdmIFN-γ) concomitant with L. pneumophila. We observed a 10-fold decrease in lung bacterial CFU at day 2 in the AdmIFN-γ-treated group compared to controls (P < 0.01). Alveolar macrophages isolated from AdmIFN-γ-treated animals displayed enhanced killing of intracellular L. pneumophila organisms ex vivo. Similar improvements in bacterial clearance were observed with i.t. recombinant IFN-γ treatment. The transient transgenic expression of IL-12, a known inducer of IFN-γ and promoter of T1-type immune responses, resulted in more modest improvement in bacterial clearance (sixfold reduction;P < 0.05). These results demonstrate that, even in immunocompetent hosts, exogenous administration or transient transgenic expression of IFN-γ, and to a lesser extent IL-12, may be of potential therapeutic benefit in the treatment of patients withLegionella pneumonia.