Expression of viral proteins may result in susceptibility of cells to the cytotoxic effect of Tumor Necrosis Factor Alpha (TNF). While murine C127 cells containing the bovine papillomavirus type 1 (BPV-1) genome were reported to exhibit increased TNF sensitivity, the gene(s) responsible was not identified. The BPV-1 E6 oncoprotein induces tumorigenic transformation of murine C127 cells and stimulates transcription when targeted to a promoter. BPV-1 E6 was introduced into C127 cells (PBE6) by retroviral infection and stable clones were isolated. These cells showed increased apoptosis in response to TNF, as measured by several criteria. TNF-induced apoptosis in PBE6 cells was accompanied by increased release of arachidonic acid, indicating that phospholipase A2 was activated. We also provide evidence that BPV-1 E6 mediated-sensitization of cells to TNF-induced apoptosis can occur in the absence of p53.