Tumor necrosis factor-alpha (TNF-alpha) can elicit many cellular responses including programmed cell death or apotosis. TNF-alpha-induced apoptosis has been largely attributed to the p60 TNF-R1 receptor. The role of p80 in TNF-alpha-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-kappaB 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.