Many diverse activities of tumor necrosis factor (TNF) are signaled through TNF receptor 1 (TNFRl). We have identified a novel 34 kDa protein, designated TRADD, that specifically Interacts with an Intracellular domain of TNFRl known to be essential for mediating programmed cell death. Overexpression of TRADD leads to two major TNF-Induced responses, apoptosis and activation of NF-KB. The C-terminal 118 amlno acids of TRADD are sufficient to trigger both of these activities and likewise sufficient for Interaction with the death domain of TNFRl. TRADD-mediated cell death can be suppressed by the crmA gene, which encodes a specific Inhibitor of the interleukin-1 f&converting enzyme. However, NF-KB activation by TRADD is not Inhibited by crmA expression, demonstrating that the signaling pathways for TNF-Induced cell death and NF-KB actlvation are distinct.