EBV has been associated with several malignancies in humans. EBV can also infect marmoset B lymphocytes, which, as opposed to human B cells, are permissive for lytic Epstein-Barr viral replication. Mice with a severe combined immunodeficiency phenotype (SCID mice) are extremely susceptible to EBV-induced lymphomagenesis when inoculated with EBV-infected lymphocytes. We inoculated SCID mice with human and marmoset lymphoblastoid cells infected with the same EBV isolates. The marmoset cells never gave rise to lymphomas, even after the administration of acyclovir or an anti-natural killer cell antibody and observation periods of up to 16 wk. In contrast, the human lymphoblastoid cells nearly always gave rise to lymphomas within 8 wk. Furthermore, human lymphoblastoid cells genetically engineered to permit lytic EBV replication also readily formed tumors in the SCID mouse. Thus, in this system, it is the cellular milieu that is crucial in determining whether a given lymphoblastoid cell will give rise to a tumor, not the EBV isolate harbored by the cell or whether the virus is permitted to undergo lytic replication.