Avian influenza A viruses of the H7 subtype have resulted in more than 100 cases of human infection since 2002. Highly pathogenic avian influenza (HPAI) H7 viruses have the capacity to cause severe respiratory disease and even death; however, the induction of the human innate immune response to H7 virus infection has not been well characterized. To better understand H7 virus pathogenesis in the human respiratory tract, we employed a polarized human bronchial epithelial cell model and primary human monocyte-derived macrophages. Here, we show that infection with HPAI H7 viruses resulted in a delayed and weakened production of cytokines, including the type I interferon response, compared with infections of other influenza A subtypes, including H7 viruses of low pathogenicity. These studies revealed that H7 viruses vary greatly in their ability to activate host innate responses and may contribute to the virulence of these viruses observed in humans. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.