Epstein-Barr virus (EBV)-induced lymphoproliferative disease (lpd) is a B cell neoplasm that affects patients who are immunosuppressed in the context of organ transplantation or HIV infection. A model for the aggressive form of this entity was generated by xenotransplantation of SCID mice with human peripheral blood leukocytes from individuals with prior contact with EBV. This model, where large B cell lymphoma occurs, was used to test the hypothesis that IL-6 has a major role in EBV-induced B cell tumorigenesis. IL-6 is known to differentiate B cells into immunoglobulin-secreting plasma cells and induce EBV replication, and xenochimeric animals have detectable serum levels of human IL-6. Human IL-6 inhibition with a neutralizing monoclonal antibody decreased tumor incidence from 62 % to 27 %. In addition, anti-IL-6 treatment significantly improved xenotransplanted animal survival, with median survival at > 245 days when compared to that of controls at 132 days. In conclusion, IL-6 plays a critical role in the pathogenesis of EBV-induced human lpd, and IL-6 inhibition may represent a new and promising preventive or therapeutic approach against this malignancy.