I nfluenza A viruses (IAVs) cause substantial morbidity and mortality in yearly epidemics, which result from the ability of the virus to alter the antigenicity of its envelope proteins. Despite the rapid replication of this virus and its ability to infect a wide variety of cell types, viremia is rare and the infection is generally limited to the upper respiratory tract. The preimmune host defense response against IAV is generally, therefore, successful. We have previously provided (and summarized) evidence that neutrophils contribute to defense against IAV, although neutrophil dysfunction and local tissue damage may be less salutory byproducts of this response. Here we provide evidence that the serum lectin mannose-binding protein directly inhibits hemagglutinin activity and infectivity of several strains of IAV. In addition mannose-binding protein acts as an opsonin, enhancing neutrophil reactivity against IAV. Opsonization of IAV by mannose-binding protein also protects the neutrophil from IAV-induced dysfunction. These effects are observed with physiologically relevant concentrations of mannose-binding protein. Two different allelic forms of recombinant mannose-binding protein are found to have similar effects. We believe, on the basis of these data, that mannose-binding protein alone and in conjunction with phagocytic cells is an important constituent of natural immunity (i.e., preimmune defense) against IAV.