We examined the expression of the Epstein-Barr virus (EBV)-induced proteins (LMP [latent membrane protein], EBNA-2, and CD23) and a lytic protein, viral capsid antigen (VCA), in five acquired immune deficiency syndrome (AIDS)-related primary CNS lymphomas (PCNSLs). We compared that expression with the expression of the same proteins in PCNSL from six immunocompetent patients and severe combined immune deficiency (SCID) mouse brains injected with EBV-infected lymphoblastoid cell lines (LCLs). Brain biopsy tissue from an AIDS patient with progressive multifocal leukoencephalopathy (PML) and a normal brain was also studied. Three of the AIDS PCNSLs expressed both human immunoglobulin kappa and lambda light chains and two expressed lambda light chain only. All non-AIDS-related PCNSLs expressed a single light-chain isotype. All five AIDS-related PCNSLs expressed LMP-1 (>40%), EBNA-2 (>60%), and VCA (1 to 5%) of tumor cells. These proteins were similarly expressed in the SCID/human chimeras. None of the PCNSLs from immunocompetent subjects, the normal brain, or the brain of the patient with PML expressed theso proteins. PCNSL in AIDS patients bears greater similarity to EBV-infected LCLs than to PCNSL from immunocompetent patients.