Histamine is a biogenic amine that influences many immune cells. In this study, we investigated the effect of histamine on the pathogenesis of 2009 pandemic H1N1 influenza virus in pigs. Histamine was not detected in the tracheal tissues of infected pigs, and no difference was found in the pathological damage found in infected pigs with and without treatment with a histamine antagonist. Lung tissues from untreated infected pigs showed severe interstitial pneumonia with accumulation of histamine, in contrast to those from infected pigs that were treated with the histamine antagonist. The expression of inflammatory cytokines was much higher in the lungs of untreated infected pigs than in infected pigs treated with the histamine antagonist. These data suggest that histamine necessary for the development of the severe pneumonia in infected pigs.