Infectious pancreatic necrosis virus (IPNV) is a major pathogen in the aquaculture industry worldwide. Factors contributing to IPNV pathogenicity are yet poorly understood. Indications of IPNV being able to evade or counteract innate host defense come from its lack of ability to induce strong type I interferon (IFN) responses in cell culture. We show here that addition of salmon rIFN-alpha1 to cells prior to IPNV infection halts the viral protein synthesis and prevents processing of pVP2 into mature VP2. Furthermore, compared to pre-treatment with IFN-alpha1 the antiviral state in cells infected with IPNV prior to IFN-treatment, was antagonized by IPNV, as detected by higher viral titers, faster viral protein synthesis and also by reduced Mx expression. The longer headstart the virus gets, the more prominent is the weakening of IFN signaling. IPNV VP4 and VP5 inhibit IFN-induced expression from the Mx promoter, indicating that these proteins contribute to the antagonistic effect.