Interferons (IFNs) play a critical role as a first line of defence against viral infection. The poxvirus Orf virus (OV) infects keratinocytes and induces acute pustular skin lesions of sheep and is transmissible to man. Keratinocytes act as immune sentinels within skin and sense viruses via their pattern recognition receptors (PRRs). Intracellular signaling cascades triggered by these PRRs leads to the production of a range of factors including type 1 and 3 IFNs. IFNs induce the anti-viral state in neighboring cells via the activation of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway that leads to the production of hundreds of IFN stimulated genes (ISGs) that block viral replication. Poxviruses are particularly adept at counteracting host antiviral responses. Cells sense viruses through intracellular RNA and DNA receptors and we have shown that OV potently blocks the expression of IFN-β in a range of cells stimulated with the synthetic polymer poly (d.A/d.T). In addition, we have shown that OV modulates the JAK/STAT pathway. The human gene GBP1 is stimulated exclusively by type II IFN while MxA is stimulated exclusively in response to type 1 IFNs. We found that GBP1 and MxA were strongly inhibited in OV infected HeLa cells stimulated with IFN-γ or IFN-α respectively. Further OV infection affected STAT1 phosphorylation in IFN-γ or IFN-α treated HeLa cells. We found that OV reduced the levels of phosphorylated STAT1 in a dose-dependent manner and was specific for Tyr701 but not Ser727. We have also shown that OV replicates in cells in which the IFN effector response is constitutively active and in cells stimulated with IFN-β. Our data shows that OV has evolved strategies to inhibit IFN expression, signaling, and the effector response.