Tumor necrosis factor (TNF) and the members of the interferon (IFN) family are major inducible cytokines that function to counteract viral infections or cellular transformation. Recently, our lab has characterized a novel antiviral state which is induced in primary human fibroblasts by co-treatment with TNF plus IFNβ. Here, we demonstrate that this synergistic state is both antiviral and cytostatic for primary human cells. Significantly, we observed that a wide spectrum of transformed human cancer cells have universally lost the ability to induce the TNF/IFNβ synergistic state, as defined by three separate criteria. We hypothesize that the ability to induce the TNF/IFNβ synergistic state is a unique feature of primary cells and is incompatible with cellular immortalization and/or transformation.