RNAi is a critical component of many cellular anti-viral responses in plants, invertebrates, and mammals. However, its in vivo role in host protection from the negative sense RNA virus Influenza Type A is unclear. Here we have examined the role of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double knock out mice, deficient in components of the RNA induced silencing complex. Compared to littermate controls, flu-infected double knock out mice exhibited increased mortality, consistent with more severe alveolitis and pneumonitis. These data indicate that optimal resistance to flu requires Argonaute 1 and/or 3. Enhanced mortality of double knock out mice was associated neither with increased viral replication nor with differential pulmonary recruitment or function of innate and adaptive immune cells. Given the absence of detectable immune defects, our results support the notion that the enhanced flu susceptibility of DKO mice arises from an intrinsic impairment in the ability of lung cells to tolerate flu-elicited inflammation.