Technical Abstract: Viruses have evolved multiple mechanisms to evade the innate immune response, particularly the actions of interferons (IFN). We have previously reported that exposure of dendritic cells (DCs) to foot-and-mouth disease virus (FMDV) in vitro yields no infection and induces a strong IFN response indicating DCs may play a critical role in the innate response to the virus. In vivo, FMDV induces lymphopenia and reduced T cell proliferative responses to mitogen, viral effects that may contribute to evasion of early immune responses. In this study we analyzed the in vivo effects of FMDV infection on the innate response of two populations of dendritic cells. During the acute phase of infection of swine, production of IFNa from monocyte-derived DCs (MoDCs) and skin-derived DCs (skin DCs) is inhibited. This effect is concurrent with rising viral titer in the blood, however, these cells are not productively infected. Interestingly, there are no changes in the capability of these DCs to uptake particles and process antigens indicating that the antigen presenting cell function is normal. The inhibition of the innate response of dendritic cell populations in the blood and skin may enhance viral pathogenesis in infected animals.