To determine the role of interferon (IFN)–γ in pneumonia, IFN-γ receptor–deficient (IFN-γ R−/−) and 129/Sv (wild-type [wt]) mice were inoculated intranasally with Streptococcus pneumoniae. Although mortality did not differ between the groups 48 h after inoculation, IFN-γ R−/− mice had significantly fewer pneumococci in their lungs than the wt mice. Similarly, IFN-γ−/− mice had fewer colony-forming units in lungs than wt mice. The relatively increased resistance of IFN-γ R−/− mice was not related to favorable effects on defense mechanisms known to contribute to antibacterial immunity—that is, the neutrophilic influx was reduced and the cytokine and nitric oxide levels were similar or lower in IFN-γ R−/− mice. In contrast, mice treated with anti–IFN-γ did not demonstrate a consistently altered bacterial outgrowth, compared with mice treated with a control antibody. These data suggest that endogenous IFN-γ, despite its protective role in defense against intracellular pathogens, does not serve a protective role during pneumococcal pneumonia