Bovine respiratory syncytial virus (BRSV) is able to counteract the alpha/beta interferon (IFN-alpha/beta)-mediated antiviral response for efficient replication in a host-specific manner. Mice models have been developed for experimental infection with human, but not bovine, respiratory syncytial virus strains. Here, it is shown that BRSV can replicate efficiently on primary cell cultures derived from type I IFN receptor-deficient, but not from wild-type IFN-competent, mice. However, BRSV infection was not enhanced in mice devoid of the type I IFN receptor. These results show that type I IFN is a major host-range determinant for infection at the cellular level, but that other factors control virus replication and pathology in vivo.