Epstein-Barr virus (EBV) carrying malignant lymphomas of the central nervous system are increasing owing to the increasing numbers of immunodeficient patients. To further understand the pathogenesis of these tumors, we studied the invasiveness of four EBV-immortalized lymphoblastoid cell lines in the brains of immunodeficient mice and the expression of adhesion molecules during this process. We injected four EBV-infected human lymphoblastoid cell lines intracerebrally into nude as well as SCID/SCID CB17 mice. Within 13 to 14 days, lethal brain lymphoproliferative lesions resulted in SCID mice, whereas similar lesions developed in 21 to 24 days in nude mice. Atypical large lymphoid cells aggressively infiltrated brain parenchyma, ventricular, and subarachnoid spaces. No difference in invasiveness was found between the monoclonal lymphoblastoid cell lines grown in long-term culture and polyclonal lymphoblastoid cell lines grown for a shorter duration. Tumors retained the same human immunoglobulin expression and activation antigen profile as the original cell lines. Furthermore, tumors expressed human LFA-1/ICAM-1 and the tumor blood vessels strongly expressed murine ICAM-1, but not MECA 79. Mice injected intracerebrally with peripheral blood leukocytes or normal bone marrow cells from an EBV seronegative individual failed to form tumors confirming the pivotal role for EBV in this process. SCID mice offer advantages for studying central nervous system lymphoproliferative disease.