Several members of the tumour necrosis factor receptor (TNF‐R) superfamily can induce cell death. For TNF‐R1, Fas/APO‐1, DR3, DR6, TRAIL‐R1 and TRAIL‐R2, a conserved ‘death domain’in the intracellular region couples these receptors to activation of caspases. However, it is not yet known how TNF receptor family members lacking a death domain, such as TNF‐R2, CD40, LT‐βR, CD27 or CD30, execute their death‐inducing capability. Here we demonstrate in different cellular systems that cytotoxic effects induced by TNF‐R2, CD40 and CD30 are mediated by endogenous production of TNF and autotropic or paratropic activation of TNF‐R1. In addition, stimulation of TNF‐R2 and CD40 synergistically enhances TNF‐R1‐induced cytotoxicity. These findings describe a novel pro‐apoptotic mechanism induced by some members of the TNF‐R family.