AbstractWe have identified three distinct cell phenotypes with respect to the conditions under which cells became susceptible to TNF‐mediated lysis. These conditions include:1) treatment with the protein synthesis inhibitor, cycloheximide;2)contact with activated macrophages, and3)infection with vaccinia virus. Whereas vaccinia virus‐infected 3T3 cells became sensitive to soluble TNF, F5b cells required contact with activated macrophages. We showed that the “macrophage‐resistant” F5m cells did not become sensitive to TNF or to killing by activated macrophages after infection with vaccinia virus. Therefore, vaccinia infection does not sensitize all cells to TNF. We also determined the pathways of lysis for cells after sensitization. Whereas 3T3, LM929, and F5b cells were killed by the process of necrosis, F5m cells lysis was characterized by the release of low mol wt DNA fragments (apoptosis).