Epstein-Barr virus has been implicated in the pathogenesis of primary brain lymphoma in patients with congenital or acquired immunodeficiency states. To examine its role in central nervous system (CNS) lymphoma in the immunocompetent host, Epstein-Barr virologic studies were performed in six consecutive cases seen at our institutions. Virus DNA sequences were detected in only one of three tumor specimens studied by Southern blot hybridization. Serologic studies from the entire cohort disclosed past virus infection; however, antibody reactivity to virus-specific antigens in cerebrospinal fluid was limited to the patient harboring genome-positive tumor. Immunologic studies revealed hyperimmunoglobulin-E (range, 720 to 1040 micrograms/ml) in each of four patients tested. Our findings suggest that Epstein-Barr virus is an infrequent pathogen in nonimmunosuppressed patients with primary CNS lymphoma. Abnormalities in isotype-specific regulation of IgE production are common in such patients and may have pathogenetic implications.