TWEAK is a recently cloned novel member of the TNF ligand family. Here we show that soluble TWEAK is sufficient to induce apoptosis in Kym‐1 cells within 18 h. TWEAK‐induced apoptosis is indirect and is mediated by the interaction of endogenous TNF and TNF receptor (TNFR)1, as each TNFR1‐Fc, neutralizing TNF‐specific antibodies and TNFR1‐specific Fab fragments efficiently antagonize cell death induction. In addition to this indirect mode of action, co‐stimulation of Kym‐1 cells with TWEAK enhances TNFR1‐mediated cell death induction. In contrast to TNF, TWEAK does only modestly activate NF‐κB or c‐jun N‐terminal kinase (JNK) in Kym‐1 cells. Although TWEAK binding to Kym‐1 cells is easily detectable by flow cytometric analysis, we found neither evidence for expression of the recently identified TWEAK receptor Apo3/TRAMP/wsl/DR3/LARD, nor indications for direct interactions of TWEAK with TNFR. Together, these characteristics of TWEAK‐induced signaling in Kym‐1 cells argue for the existence of an additional, still undefined non‐death domain‐containing TWEAK receptor in Kym‐1 cells.