The purpose of this study was to examine the 100-fold difference in mycoplasma levels in lungs of gamma interferon knockout (IFN-γ -/-) mice compared to those seen with wild-type BALB/c mice at 3 days postinfection. NK cells secreted IFN-γ; however, their cytotoxic granule extracts failed to kill mycoplasma. We found a conundrum: the clearance of organisms was as effective in NK-depleted IFN-γ-/- animals as in wild-type mice (with both IFN-γ and NK cells). NK+ IFN-γ-/- animals had high mycoplasma burdens, but, after NK-like cell depletion, mycoplasma numbers were controlled. Essentially, IFN-γ was important in animals with NK-like cells and unimportant in animals without NK cells, suggesting that IFN-γ counters deleterious effects of NK-like cells. Impairment of innate immunity in IFN-γ -/- mice was not due to NK-like cell killing of macrophages. The increased levels of inflammatory cytokines and neutrophils in lung fluids of NK+ IFN-γ-/- mice were reduced after NK cell depletion. In summary, in the murine model that resembles chronic human disease, innate immunity to mycoplasma requires IFN-γ when there are NK-like cells and the positive effects of IFN-γ counteract negative elects of NK-like cells. When imbalanced, NK-like cells promote disease. Thus, it was not the lack of IFN-γ but the presence of a previously unrecognized NK-like cell-suppressive activity that contributed to the higher mycoplasma numbers. It appears that pulmonary NK cells may contribute to the immunosuppressive environment of the lung, but when needed, these dampening effects can be counterbalanced by IFN-γ. Furthermore, there may be instances where perturbation of this regulatory balance contributes to the susceptibility to and severity of disease.