INTRODUCTION: Obesity significantly increases the risk of death following an influenza virus infection. Consistent with these clinical observations, we and others have shown that mice with diet-induced obesity develop much more severe influenza than their lean-fed counterparts. Traditionally, it has been assumed that this increased susceptibility can be reversed by weight loss. However, this remains to be tested experimentally. METHODS: Here, a novel mouse model was developed to study the long-term effects of obesity on anti-viral immunity. Four week old C57BL/6 mice were fed a high fat or lean diet for 10 weeks. After 10 weeks, mice fed a high fat diet had a significantly higher total body weight and percentage body fat compared to mice fed the lean diet. Obese mice were then swapped to a lean diet for 10 weeks. RESULTS: After 10 weeks on the lean diet, mice that were previously obese (PO) had an equivalent body weight and percentage body fat to mice that received the lean diet for the entirety of the 20 week treatment period. However, upon infection with influenza virus (A/Auckland/09(H1N1)), PO mice displayed increased viral replication, inflammation, body weight loss and pulmonary dysfunction compared to lean-fed mice. Cells in the lung lumen of PO mice also had an altered metabolic state compared to those of lean fed mice. Importantly, in mice deficient in the NLRP3 inflammasome, obesity had no long term effect on susceptibility to influenza virus infection. CONCLUSIONS: We propose that obesity can have long-term, NLRP3 dependent, effects on the metabolism of innate inflammatory cells such that they are impaired in their anti-viral response. Understanding the long-term effects that obesity has on anti-viral immunity will help pave the way for the development of novel therapeutics to improve the health of the billions of people who are, or previously have been, obese.