AbstractEpstein–Barr virus (EBV) establishes lifelong latency in B‐lymphocytes following infection. Although in immune‐competent individuals EBV remains in a quiescent state, in immunodeficient individuals, such as those with AIDS or transplant recipients, B‐lymphocytes infected with EBV proliferate to give rise to lymphoproliferative diseases. Similarly, in vitro, EBV transforms human B‐lymphocytes into indefinitely growing lymphoblastoid cell lines (LCLs) in the absence of cytotoxic T‐lymphocytes. Although LCLs harbor the entire EBV genome as an episome, in most cells the virus remains in a latent state expressing a fraction of EBV genes, and lytic infection occurs spontaneously but only in a small percentage of cells. Here, we report that lytic infection contributes to EBV‐induced lymphoproliferation by a paracrine mechanism. An EBV immediate‐early protein, BZLF1, induces IL‐13, thus facilitating the proliferation of EBV‐transformed B‐lymphocytes in the presence of T‐lymphocytes. These data suggest that lytic gene products could contribute to virus‐induced oncogenesis by a paracrine mechanism. J. Med. Virol. 84:504–510, 2012. © 2011 Wiley Periodicals, Inc.