Resveratrol (3,4 0 ,5-trihydroxy-trans-stilbene), a polyphenolic natural product, shows chemopreventive properties against several cancers, heart diseases, inflammation, and viral infections. Epstein Barr virus (EBV), a g-herpesvirus, contributes to the development of several human cancers including Burkitt's lymphoma (BL). In this study, we asked whether treatment with resveratrol would affect the viability of EBV-positive BL cells displaying different forms of latency. We report here that resveratrol, regardless of EBV status, induces caspasedependent apoptosis by arresting cell-cycle progression in G 1 phase. However, resveratrol strongly induced apoptosis in EBV(À) and latency I EBV(þ) cells, whereas latency II and latency III EBV(þ) BL cells showed a survival advantage that increased with the extent of the pattern of viral gene expression. Resveratrol-induced cellcycle arrest and apoptosis occurred in association with induction of p38 MAPK phosphorylation and suppression of ERK1/2 signaling pathway. Moreover, NF-kB DNA-binding activity was inhibited in all BL lines except EBV (þ) latency III cells.LMP1 oncogene, which is expressed in latency III phenotype, is involved with the higher resistance to the antiproliferative effect of resveratrol because siRNA-mediated inhibition of LMP1 greatly increased the sensitivity of latency III BL cells as well as that of lymphoblastoid cell lines to the polyphenol. We propose that a combined resveratrol/siRNA strategy may be a novel approach for the treatment of EBV-associated B-cell malignancies in which the viral pattern of gene expression has been defined. Mol Cancer Res; 9(10); 1346-55. Ó2011 AACR.