Abstract Transforming growth factor β (TGF-β) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. However, the exact mechanism through which TGF-β induces cell death is still unknown. We examined a potential role of various death receptor/ligand systems in TGF-β–induced apoptosis and identified the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a mediator of TGF-β–induced apoptosis in hepatoma cells. TGF-β–induced apoptosis is significantly impaired upon blockage of TRAIL. We show that TRAIL is upregulated in hepatoma cells upon treatment with TGF-β, whereas TRAIL receptor levels remain unchanged. In conclusion , our results provide evidence that the TRAIL system is critically involved in TGF-β–induced cell death in liver pathology. (Hepatology 2005;42:183–192.)