Many cells latently infected with Epstein-Barr virus (EBV), including certain virus-associated tumors, express latent membrane protein 2A (LMP2A) suggesting an important role for this protein in viral latency and oncogenesis. LMP2A mimics B-cell receptor signaling but can also act as a decoy receptor blocking B-cell receptor (BCR) activation. Studies of peripheral B cells have not resolved this apparent contradiction because LMP2A seems to be dispensable for EBV-induced transformation of these B cells in vitro. We show here that LMP2A is essential for growth transformation of germinal center B cells, which do not express the genuine BCR because of deleterious somatic hypermutations in their immunoglobulin genes. BCR-positive (BCR(+)) and -negative (BCR(-)) B cells are readily transformed with a recombinant EBV encoding a conditional, floxed LMP2A allele but the survival and continued proliferation of both BCR(+) and BCR(-) B cells is strictly dependent on LMP2A. These findings indicate that LMP2A has potent, distinct anti-apoptotic and/or transforming characteristics and point to its role as an indispensable BCR mimic in certain B cells from which human B-cell tumors such as Hodgkin's lymphoma originate.