Five patients with advanced AIDS developed a unique type of high grade primary body cavity-based non-Hodgkin's lymphoma (NHL). The lymphomas were exclusively in serous effusions with no detectable mass disease in the body cavities and no lymphadenopathy or organomegaly. All of the lymphomas exhibited virtually identical morphology, which could not be precisely classified, but appeared to bridge features of large cell immunoblastic and anaplastic large cell lymphomas. Immunophenotypically the lymphoma cells lacked expression of any B- or T-lymphocyte antigens, but expressed CD45 and the activation antigens CD30, CD38, CD71, and HLA-DR. Clonally rearranged immunoglobulin heavy chain and kappa light chain genes were identified by Southern blot analysis. Molecular studies also revealed Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) genomes and germline configuration of the c-myc protooncogene. In two cases studied cytogenetically, the lymphoma cells manifested complex chromosome abnormalities. These lymphomas are clinically and biologically unique and found predominantly in patients with advanced AIDS, in many cases with pre-existing Kaposi's sarcoma.