Viruses have evolved multiple mechanisms to evade the innate immune response, particularly the actions of interferons (IFNs). We have previously reported that exposure to dendritic cells (DCs) to foot-and-mouth disease virus (FMDV) in vitro yields no infection and induces a strong type I IFN (IFN-α and IFN-ß) response, indicating that 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 evasive of early immune responses. In this study we analyzed the in vivo effects of FMDV infection on the IFN-α response of two populations of dendritic cells. During the acute phase of infection of swine, production of IFN-α from monocyte-derived DCs (MoDCs) and skin derived DCs (skin DCs) is inhibited. This effect occurs concurrently with with rising viral titers in the blood; however, these cells are not productively infected. Interstingly, there are no changes in the capability of these DCs to take up particles and process antigens, indicating that antigen-presenting cell function is normal. These data indicate that inhibition of the IFN-α response of dendritic cell populations from blood and skin by FMDV enhances viral pathogensesis in infected animals.