Patients infected with human immunodeficiency virus are prone to a wide variety of lymphoproliferative disorders. In these patients the clinical presentation of malignant lymphoma often overlaps with that of benign lymphoid proliferations. Both may include lymphadenopathy, splenomegaly, blood and bone marrow dyscrasias, and lymphocyte-rich effusions. Because benign and malignant lymphocyte-rich effusions, as well as effusions from other malignancies, may contain large cells that resemble immunoblasts or Burkitt's cells, cytomorphologic characteristics alone are unreliable for definitive diagnosis of malignant lymphoma. Usual immunotyping panels using antibodies to B- and T-cell markers frequently fail to demonstrate cell lineage in lymphoma cells of patients with acquired immune deficiency syndrome (AIDS). The authors used gene rearrangement to confirm the diagnosis of malignant lymphoma in effusions from three patients with AIDS when routine cell marker studies failed to demonstrate cell lineage or clonality. Use of biotinylated probes eliminated the need for handling radioactive material and enabled performance of studies in a routine immunohistochemistry laboratory.