It has been reported that host defense against pulmonary K. pneumoniae infection requires IL-22, which has been proposed to be of T cell origin. Supporting a role for IL-22, we found that Il22−/− mice had decreased survival as compared with wild type mice after intratracheal infection with K. pneumoniae. Surprisingly, however, Rag2−/− mice did not differ from wild type mice in survival or levels of IL-22 in the lungs after infection with K. pneumoniae. By contrast, K. pneumoniae-infected Rag2−/−Il2rg−/− mice failed to produce IL-22. These data suggested a possible role for NK cells or other innate lymphoid cells (ILC) in host defense and production of IL-22. Unlike NK cell-like ILCs that produce IL-22 and display a surface phenotype of NK1.1−NKp46+CCR6+, lung NK cells showed the conventional phenotype, NK1.1+NKp46+CCR6−. Mice depleted of NK cells using anti-asialo GM1 showed decreased survival and higher lung bacterial counts as well as increased dissemination of K. pneumoniae to blood and liver as compared with control-treated mice. NK cell depletion also led to decreased production of IL-22 in the lung. Within one day after infection, although there was no increase in the number of lung NK cells, a subset of lung NK cells became competent to produce IL-22, and such cells were found in both wild type and Rag2−/− mice. Our data suggest that during pulmonary infection of mice with K. pneumoniae, conventional NK cells are required for optimal host defense, which includes the production of IL-22.