In summary, we have shown that stimulation of lung mucosal innate immunity with a complex bacterial lysate confers striking protection against a virulent viral pathogen. Resistance to influenza is stimulated despite profound induction of lungrestricted inflammation, suggesting that excessive pulmonary inflammation is not the primary cause of influenza-induced mortality. Further, we found that the same treatment can be combined in the post-exposure setting with antiviral medication to improve survival. Taken together, we infer that therapeutic manipulation of StIR may be possible to reduce the mortality burden associated with viral pneumonias, and potentially, to protect the population against bioterror attacks.