Latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus (EBV) is a membrane protein that activates multiple signaling pathways and transcription factors, including NF-kappaB. Our recent report demonstrated that expression of LMP1 induced programmed cell death in an NF-kappaB-dependent manner. In this study, we demonstrate that a variant CAO-LMP1 derived from EBV-infected nasopharyngeal carcinoma (NPC) does not induce cell death unlike the prototype B95.8-LMP1, although both types of LMP1 show NF-kappaB activation to a similar extent. Studies with chimeric or mutated proteins identified two amino acids in the transmembrane domain, which are commonly substituted in NPC-derived LMP1 variants, being critical for cell death induction by B95.8-LMP1. Furthermore, we show that the B95.8 transmembrane domain co-operates with NF-kappaB to trigger cell death program. Thus, our results reveal a particular feature of the transmembrane domain of tumor-derived CAO-LMP1 and suggest its possible contribution to the pathogenesis of NPC.