Tumor necrosis factor‐α (TNF‐α) can elicit many cellular responses including programmed cell death or apotosis. TNF‐α‐induced apoptosis has been largely attributed to the p60 TNF‐R1 receptor. The role of p80 in TNF‐α‐mediated apoptosis is largely unknown. We now present evidence that signaling through p80 switches on the previously dormant apoptotic machinery associated with p60. This effect on p60‐associated apoptosis involves the proximal activation of caspases and proceeds in the presence of strong NF‐κB induction. We evaluated the role of TRAF2 in p80‐assisted apoptosis and found that a decrease in TRAF2 protein occurs with p80 but not p60 stimulation. However, the decrease in TRAF2 protein can be dissociated from apoptosis in the presence of a caspase inhibitor. Hence, one means by which p80 TNF‐R2 regulates apoptosis is through its ability to amplify internally apoptotic signal transduction from p60 TNF‐R1.