Primary effusion lymphoma (PEL), and its solid counterpart, extracavitary PEL, is a rare, but unique, clinicopathologic entity, which is pathogenetically related to infection with the gamma herpesvirus, Kaposi sarcoma herpesvirus/human herpes virus 8. Although it occurs primarily in individuals positive for human immunodeficiency virus infection with low CD4 counts, it can develop in other patient populations as well. The tumor cells, which are morphologically pleomorphic, are usually positive for Epstein-Barr virus infection, classically lack expression of B- and T-cell–associated antigens, and are often positive for activation antigens such as CD30 and epithelial membrane antigen. Molecular studies show that they are of B-cell origin but usually lack structural alterations in oncogenes and tumor suppressor genes such as MYC. However, without attention to clinical history, careful examination of the cytomorphology and investigation for the presence of Kaposi sarcoma herpesvirus/human herpes virus 8, PEL/EC-PEL may be misdiagnosed or unrecognized. Here a case of PEL occurring in a patient positive for human immunodeficiency virus infection is described with a discussion of the pertinent cliniopathologic features of this unique entity.