Oncolytic viruses obliterate tumor cells in tissue culture but not against the same tumors in vivo. We report that macrophages can induce a powerfully protective antiviral state in ovarian and breast tumors, rendering them resistant to oncolytic virotherapy. These tumors have activated JAK/STAT pathways and expression of interferon-stimulated genes (ISGs) is upregulated. Gene expression profiling (GEP) of human primary ovarian and breast tumors confirmed constitutive activation of ISGs. The tumors were heavily infiltrated with CD68+ macrophages. Exposure of OV-susceptible tumor cell lines to conditioned media from RAW264.7 or primary macrophages activated antiviral ISGs, JAK/STAT signaling and an antiviral state. Anti-IFN antibodies and shRNA knockdown studies show that this effect is mediated by an extremely low concentration of macrophage-derived IFNβ. JAK inhibitors reversed the macrophage-induced antiviral state. This study points to a new role for tumor-associated macrophages in the induction of a constitutive antiviral state that shields tumors from viral attack.