The unparallelled spread of highly pathogenic avian influenza A (HPAI) H5N1 viruses has resulted in devastating outbreaks in domestic poultry and sporadic human infections with a high fatality rate. To better understand the mechanism(s) of H5N1 virus pathogenesis and host responses in humans, we utlized a polarized human bronchial epithelial cell model that expresses both avian alpha-2,3 and human alpha-2,6 linked sialic acid receptors on the apical surface and supports productive replication of both H5N1 and H3N2 viruses. Using this model, we compared the ability of selected 2004 HPAI H5N1 viruses isolated from humans and a recent human H3N2 virus to trigger the type I interferon response. H5N1 viruses elicited significantly less IRF3 nuclear translocation, as well as delayed and reduced production of IFNbeta compared with the H3N2 virus. Furthermore, phosphorylation of Stat2 and induction of interferon-stimulated genes (ISGs), such as MX1, ISG15, IRF7 and RIG-I, were substantially delayed and reduced in cells infected with H5N1 virus. We also observed that the highly virulent H5N1 virus replicated more efficiently and induced a weaker interferon response than the H5N1 virus that exhibited low virulence in mammals in an earlier study. Our data suggest that the H5N1 viruses tested, especially the virus with the high pathogenicity phenotype, possess greater capability to attenuate type I IFN response compared with the human H3N2 virus. The attenuation of this critical host innate immune defense may, in part, contribute to the virulence of H5N1 viruses observed in humans.