The excessively expressed interferon-α (IFN-α) might contribute to the uncontrolled inflammatory responses, causing pathological damage during influenza virus infection. However, the correlation of the pathological damage with the expression profile of IFN-α subtypes in the focus of infection with influenza viruses is poorly understood. To investigate this, we detected the IFN-α subtype dominance in human respiratory epithelial cells and mouse lungs, both of which were infected with influenza viruses. It was found that IFN-α1, IFN-α6, IFN-α14, and IFN-α16 were dominantly expressed in respiratory epithelial cells from the patients infected with IAV, whereas IFN-α5, IFN-α8, and IFN-α21 were dominantly expressed in respiratory epithelial cells from the patients infected with less pathogenic IBV and that IFN-α1, IFN-α9, and IFN-α15 were dominantly expressed in lungs of the mice infected with H1N1 IAV, and IFN-α2, IFN-α12, and IFN-α13 were dominantly expressed in lungs of the mice infected with less pathogenic H9N2 IAV. Compared with H9N2 IAV, H1N1 IAV induced higher mortality rates and more obvious body weight loss in the mice. In addition, IAV or H1N1 IAV induced a significantly higher level of CXCL10 mRNA in the human respiratory epithelial cells or the mouse lungs, respectively. In mice, the high level of Cxcl10 mRNA was accompanied by the abundant infiltrated neutrophils and more severe pathological changes in the lungs. Together, the data presented here indicate that the pathogenicity of influenza viruses is correlated with the IFN-α subtypes induced by influenza viruses. KEY POINTS: • Different influenza viruses induce differential inflammation responses. • Various influenza viruses induce diverse expression profiles of IFN-α subtypes. • The locally produced IFN-α subtypes correlated to the differential inflammation. Graphical abstract.Keywords: Expression profile; Infection; Influenza virus; Interferon-α subtype.