OBJECTIVES: To report a patient with primary effusion lymphoma who was negative for human herpesvirus-8 (HHV-8), human immunodeficiency virus, Epstein-Barr virus, hepatitis C virus, and hepatitis B virus, as well as review 54 reported cases of HHV-8-unrelated primary effusion lymphoma (PEL)-like lymphoma in the literature to clarify the nature of this entity. METHODS: The patients' characteristics, clinical presentation, pathogenesis, morphologic-immunophenotypic features, clinical management, and prognosis were studied. RESULTS: HHV-8-negative PEL-like lymphomas often occur in immunocompetent and elderly patients, are sometimes associated with chronic inflammation-related fluid overload, are mostly large B-cell or large B-cell with plasmacytic differentiation type, and are associated with a better prognosis. CONCLUSIONS: In various aspects, HHV-8-unrelated PEL-like lymphoma is a different entity from HHV-8-related PEL. Immunophenotype, morphology, and c-myc/8q24 status should be included for differential diagnosis. A test for c-myc or 8q24 abnormalities should be recommended for subdividing HHV-8-unrelated PEL-like lymphoma, which may have benefits in patient management.