NF-kappaB is a transcription factor known to promote or antagonize cell death depending on cell types and stimuli. Here, we demonstrate that expression of latent membrane protein 1 (LMP1), an Epstein-Barr virus (EBV)-encoded membrane protein, triggers programmed cell death in an NF-kappaB-dependent manner. Co-expression of NF-kappaB inhibitors completely prevented activation of NF-kappaB and LMP1-induced cell death. Addition therein of RelA, an active subunit of NF-kappaB, restored the NF-kappaB activation and cell death induction by LMP1, but RelA alone did not induce cell death. These results indicate that the activation of NF-kappaB is required for cell death induced by LMP1. Moreover, LMP1 induced activation of caspase-3 via the activation of NF-kappaB. Studies with z-VAD-fmk, a caspase inhibitor, indicated that NF-kappaB mediated both caspase-dependent and -independent death pathways. In conclusion, the cell death induced by LMP1 uncovered caspase-dependent and -independent death pathways both of which require NF-kappaB.