Immunohistochemistry for CD30 was positive in one patient. Immunohistochemistry for HHV-8 and in situ hybridization for Epstein-Barr virus-encoded small RNAs (EBER) was positive on cell blocks in both cases, consistent with the diagnosis of primary effusion lymphoma. PEL should be considered in the differential diagnosis of CD20-negative hematopoietic neoplasms, and flow cytometry may provide helpful clues for the diagnosis of PEL as part of the workup for pleural effusion with cytologically malignant cells. This evidence concerns the gene TNFRSF8 and primary effusion lymphoma.