Nuclear factor kappaB (NF kappaB) regulates the expression of various genes essential for cell survival. Here we demonstrate that suppression of NF kappaB nuclear import with SN50 peptide carrying the nuclear localization sequence (NLS) of the NF kappaB p50 subunit induces apoptosis in human peripheral blood T lymphocytes (T-PBL), which can be blocked with the pan-caspase inhibitor Z-VAD.fmk. However, even when caspase function is blocked, the addition of SN50 induces irreversible cell loss due to the reduction in the mitochondrial transmembrane potential (Delta Psim) followed by disruption of the cell membrane, hallmarks of necrosis. These observations demonstrate that although inhibition of NF kappaB nuclear translocation by SN50 peptide can induce caspase-dependent apoptosis in T-PBL, cell death may still proceed in the absence of functional caspase activity. The availability of downstream caspases appears to determine the mode of cell death in NF kappaB defective cells.