Background.?Obesity is associated with a high circulating leptin level and severe influenza A(H1N1)pdm09 infection. The mechanism for severe lung injury in obese patients and the specific treatment strategy remain elusive.Methods.?We studied the pathogenesis of A(H1N1)pdm09 infection in a diet-induced obese mouse model.Results.?Obese mice had significantly higher initial pulmonary viral titer and mortality after challenged with A(H1N1)pdm09 virus when compared with age-matched lean mice. Compared with lean mice, obese mice had heightened proinflammatory cytokines/chemokines and more severe pulmonary inflammatory damage. Furthermore, obese mice had a higher pre-existing serum leptin but lower pre-existing adiponectin levels. Recombinant mouse leptin increased the interleukin (IL)-6 mRNA expression in mouse lung single cell preparations, mouse macrophages and lung epithelial cell lines infected with A(H1N1)pdm09 virus. Administration of anti-leptin antibody improved the survival of infected obese mice with associated reduction in levels of lung proinflammatory cytokines IL-6 and IL-1β but not the pulmonary viral titer.Conclusion.?Our findings suggest that pre-existing high level of circulating leptin contributes to the development of severe lung injury by A(H1N1)pdm09 virus in diet-induced obese mice. The therapeutic strategy of leptin neutralization for the reduction of proinflammatory responses and pulmonary damage in obese patients warrants further investigations.