To test whether the behaviour of transcription factor NF-kappaB as a promoter or antagonist of apoptosis depends on the apoptotic stimulus, we determined the influence of NF-kappaB on cell killing elicited by a variety of inducers within a given cell type. Inhibition of NF-kappaB by genetic and pharmacological approaches rendered HeLa cells more susceptible to TNF-alpha-induced cell killing, but protected them almost completely from H2O2- and pervanadate-induced apoptosis. TNF-alpha was unable to protect HeLa from H2O2- and pervanadate-induced apoptosis and further enhanced the cytotoxicity induced by these two adverse agents. Supernatants from HeLa cells stably overexpressing a transdominant negative form of IkappaB-alpha selectively increased the cytotoxicity of TNF-alpha for HeLa cells, suggesting that the enhanced susceptibility of these cells can be attributed to one or more secretable factors. Supershift experiments showed that the various apoptotic stimuli induced the same subset of DNA-binding subunits. Therefore, the nature of the signals elicited by the respective death inducers determines whether NF-kappaB induction leads to apoptosis or survival, suggesting that the manipulation of NF-kappaB activity may provide a new approach to adjuvant therapy in cancer treatment.