To determine if fatal infections caused by different highly virulent influenza A viruses share the same pathogenesis, we compared 2 different influenza A virus subtypes, H1N1 and H5N1. The subtypes, which had shown no pathogenicity in laboratory mice, were forced to evolve by serial passaging. Although both adapted viruses evoked diffuse alveolar damage and showed a similar 50% mouse lethal dose and the same peak lung concentration, each had a distinct pathologic signature and caused a different course of acute respiratory distress syndrome. In the absence of any virus labeling, a histologist could readily distinguish infections caused by these 2 viruses. The different histologic features described in this study here refute the hypothesis of a single, universal cytokine storm underlying all fatal influenza diseases. Research is thus crucially needed to identify sets of virulence markers and to examine whether treatment should be tailored to the influenza virus pathotype.