Epstein–Barr virus (EBV) transforms B lymphocytes into lymphoblastoid cell lines usurping the Notch and tumor necrosis factor receptor pathways to effect transcription including NF-κB activation. To determine whether NF-κB activity is essential in the growth and survival of EBV-transformed lymphoblastoid cell lines, a nondegradable IκBα mutant was expressed under tetracycline regulation. Despite continued Bcl-2 and Bcl-x/L expression, NF-κB inhibition induced apoptosis as evidenced by poly(ADP-ribose) polymerase cleavage, nuclear condensation and fragmentation, and hypodiploid DNA content. Both caspase 3 and 8 activation and loss of mitochondrial membrane potential were observed in apoptotic cells. However, caspase inhibition failed to block apoptosis. These experiments indicate that NF-κB inhibitors may be useful in the therapy of EBV-induced cellular proliferation.