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Primary effusion lymphoma (PEL) is a unique recently identified non-Hodgkin’s lymphoma which was originally identified in AIDS patients. PEL is characteristically infected by the Kaposi sarcoma-associated herpesvirus (KSHV) and shows a peculiar presentation involving liquid growth in the serous body cavity with generally poor prognosis. As the NK-κB pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of biscoclaurine alkaloid, Cepharanthine, on PEL derived cell lines (BCBL-1, TY-1, and RM-P1) in vitro and in vivo. MTT assay revealed the cell proliferation of PEL cell lines was significantly suppressed by the addition of Cepahranthine (1–10μg/ml). Cepharanthine also inhibited NK-κB acitivation and induced apoptotic cell death in PEL cell lines. We established PEL animal model by intraperitoneal injection of BCBL-1 into the nobel immunodeficient NOD/Scid/Jak3null mice. Intraperitoneal injection led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, resembling the diffuse nature of human PEL. Intraperitoneal administration of Cepharanthine inhibited the ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NK-κB could be an ideal molecular target of PEL and Cepharanthine could a unique therapeutic agent for PEL.