We describe an unusual case of a body cavity-based lymphoma, otherwise termed primary effusion lymphoma (PEL), involving the atria of the heart of an HIV-seropositive patient. This is the first reported case of the involvement of the heart by this rare lymphoma. This HIV-related lymphoma represents a distinct B-cell malignancy associated with human herpesvirus-8 (HHV-8) infection. It is characterized by involvement of body cavities, with infrequent evidence of organ or bone marrow infiltration. The tumor cells are large, nucleolated with an immunoblastic or anaplastic appearance, positive for activation markers, such as CD30, and negative for B-cell and T-cell immunophenotypic markers. Integration of HHV-8 DNA sequences is considered the hallmark of PEL. The tumor demonstrates frequent association with Epstein-Barr virus (EBV) and uniform absence of c-myc oncogene rearrangement, unlike most other HIV-related lymphomas.