THE cell-killing effects of the cytokines TNF-alpha and Fast are mediated by the distinct cell-surface receptors TNFR1, TNFR2 and Fas (also known as CD95/APO-1), which are all members of a receptor superfamily that is important for regulating cell survival(1-4). The cytoplasmic regions of TNFR1 and Fas contain a conserved ’death’ domain which is an essential component of the signal pathway that triggers apoptosis and activation of the transcription factor NF-kappa B (refs 5, 6). Here we report the isolation of a 54K receptor that is a new member of the TNFR superfamily, using the death domain of TNFR1 in a yeast two-hybrid system(7,8). This protein, WSL-1, is most similar to TNFR1 itself, particularly in the death-domain region, The gene wsl-1 is capable of inducing apoptosis when transfected into 3T3 and 293 cells, and can also activate NF-kappa B in 293 cells, Like TNFR1, WSL-1 will homodimerize in yeast. WSL-1 also interacts specifically with the TNFR1-associated molecule TRADD(9). The tissue distribution is very restricted and significantly different from that of Fas and TNFR1.