Abstract Among the products of Th17 cells are IL-17A and IL-22, which are required for protection against extracellular pathogens, such as K. pneumoniae. Although published data suggest that T cells are the source of these cytokines during pulmonary infection with K. pneumoniae, we found that Rag2-/- mice did not differ from wild-type mice in survival, bacterial counts or levels of IL-22 in the lungs after intratracheal infection with K. pneumoniae. By contrast, K. pneumoniae-infected Rag2-/-γc-/- mice failed to produce IL-22 and had higher bacterial counts as compared with wild-type controls. Together, these data suggested a possible role for NK cells in host defense, and in the production of IL-22, during K. pneumoniae infection. Lung NK cells showed a conventional surface phenotype and lacked NKp46 and CCR6, markers for IL-22-producing (“NK22”) NK cells. Moreover, we found no increase in lung NK cells during infection. However, as compared with control mice, mice depleted of NK-cells using anti-Asialo GM1 showed decreased survival and higher bacterial counts, as well as increased dissemination of K. pneumoniae to blood and liver. In addition, NK cell depletion led to decreased production of IL-22 and other cytokines important for protection, including IL-12, TNF-α, and IL-6. Together, our data show that NK cells are required for defense against pulmonary K. pneumoniae infection and optimal production of protective cytokines, including IL-22. Supported by the IRP, NIH, NIAID.