Pleural effusion lymphoma (PEL) is a rare B-cell lymphoma that has a very poor prognosis with a median survival time of around 6 months. PEL is caused by Kaposi`s sarcomaassociated herpesvirus, and is often co-infected with the Epstein Barr virus. The complement system is fundamental in the innate immune system against pathogen invasion and tumor development. In the present study, we investigated the activation of the complement system in PEL cells using human serum complements. Interestingly, two widely used PEL cell lines, BCP-1 and BCBL-1, showed different susceptibility to the complement system, which may be due to CD46 expression on their cell membranes. Complement activation did not induce apoptosis but supported cell survival considerably. Our results demonstrated the susceptibility of PEL to the complement system and its underlying mechanisms, which would provide insight into understanding the pathogenesis of PEL.