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The activity of NF-κB/Rel transcription factors can inhibit the apoptosis induced by TNF, UV or cancer therapy drugs in a number of cell types, including human T lymphocytes. Furthermore, the NF-κB/Rel inducer, phorbol-12-myristate-13-acetate (PMA), has been reported to suppress the CD95-induced apoptosis of human T lymphocytes. To verify whether the survival-enhancing effect of PMA required NF-κB/Rel activity, we generated two Jurkat cell sublines (AL.7 and AL.8) transfected with a pCMV4-IκBα construct, and two (AL.3 and AL.5) with the void pCMV4 vector. Compared to wild type, AL.3 and AL.5 cells, the AL.7 and AL.8 sublines displayed markedly lower amounts of NF-κB/Rel nuclear complexes and a reduced expression of a κB-controlled CAT reporter gene after 1 and 4 h of incubation with PMA, respectively. All the five cell types displayed negligible levels of apoptosis when cultured with medium or PMA alone; when stimulated with the mAb CH-11, the AL.7 and AL.8 sublines displayed apoptotic responses only slightly ( 85% in wild type, AL.3 and AL.5 cells and by 4-fold higher than in control cells. We conclude that the inhibition of the CD95-induced apoptosis by PMA relies on both NF-κB/Rel-dependent and -independent mechanisms. The partial contribution of these nuclear factors to the suppression of apoptosis indicates that the NF-κB/Rel activity can influence the extent of the CD95-induced T cell death.