Several early pandemic H1N1 influenza isolates cause severe disease in different animals models, while most strains result in mild clinical signs similar to seasonal influenza. In this study, the pathogenesis of the virulent Mexican isolate A/Mexico/InDRE4487/2009 and a mild Canadian isolate A/Canada-AB/RV1532/2009 was compared in ferrets. These viruses differed at nine residues, none of which has been previously identified as virulence factor. The Mexican isolate caused more severe disease and higher mortality, and reached higher peak nasal wash titers. Both viruses grew similarly in the respiratory tract, but only the virulent virus was detected in the gut after day 3. During the acute phase, both strains caused similar lung pathology, however the Mexican isolate induced severe inflammation even after virus clearance. This virus was also associated with a rapid and sustained induction of inflammatory cytokines, indicating that early dysregulation of the host response contributes importantly to the disease outcome.