TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines and induces apoptosis in a wide variety of cells. Based on homology searching of a private database, a receptor for TRAIL (DR4 or TRAIL‐R1) was recently identified. Here we report the identification of a distinct receptor for TRAIL, TRAIL‐R2, by ligand‐based affinity purification and subsequent molecular cloning. TRAIL‐R2 was purified independently as the only receptor for TRAIL detectable on the surface of two different human cell lines that undergo apoptosis upon stimulation with TRAIL. TRAIL‐R2 contains two extracellular cysteine‐rich repeats, typical for TNF receptor (TNFR) family members, and a cytoplasmic death domain. TRAIL binds to recombinant cell‐surface‐expressed TRAIL‐R2, and TRAIL‐induced apoptosis is inhibited by a TRAIL‐R2–Fc fusion protein. TRAIL‐R2 mRNA is widely expressed and the gene encoding TRAIL‐R2 is located on human chromosome 8p22‐21. Like TRAIL‐R1, TRAIL‐R2 engages a caspase‐dependent apoptotic pathway but, in contrast to TRAIL‐R1, TRAIL‐R2 mediates apoptosis via the intracellular adaptor molecule FADD/MORT1. The existence of two distinct receptors for the same ligand suggests an unexpected complexity to TRAIL biology, reminiscent of dual receptors for TNF, the canonical member of this family.