The incidence of primary central nervous system lymphomas is increased several 1000-fold in AIDS patients. These are B-cell malignancies consistently associated with Epstein-Barr virus. They typically occur late in the course of HIV infection and are associated with a very short median survival. The pattern of Epstein-Barr virus gene expression is indicative of severe immunocompromise. Radiographic differentiation from toxoplasmosis remains a problem. Polymerase chain reaction amplification of Epstein-Barr virus DNA in cerebrospinal fluid, 18F-fluoro-deoxyglucose-positron emission tomography scanning, and 201-thallium single-photo emission CT are all promising noninvasive or minimally invasive diagnostic procedures that may obviate the need for brain biopsy in the future. Occasional patients have long remissions after therapy but most patients die within a few months. A possible role for combined modality therapy, including combination chemotherapy, is being explored.