Intraperitoneal injection of lymphoid cells from EBV+ donors into SCID mice might provide a useful tool for studying the pathways of B-cell lymphomagenesis in man. Since previous studies showed that donor T cells greatly favor B-cell proliferation and tumor generation in this model, we addressed the host and donor factors involved in limiting or promoting lymphoma development. The number of EBV-infected B-cell precursors was crucial, since purified B lymphocytes, which alone were unable to generate tumors, underwent expansion and established tumor masses when the animals were inoculated with an EBV-containing supernatant. Host factors were critical in limiting tumor development; in vivo NK-cell removal allowed purified B cells to expand and proceed to tumors in the absence of T lymphocytes, whereas potentiation of mouse NK-cell activity prevented tumor generation in PBMC- and LCL-injected animals. The T-cell-derived factors that favor lymphomagenesis could not be identified; IL-2, IL-4, IL-6, and soluble CD23 were not able to promote B-cell expansion, and treatment of PBMC-injected mice with the relevant anti-cytokine anti-sera did not counteract lymphoma development. These experiments also showed that IL-6 plays a minor role, if any, in B-cell lymphoproliferation in this model. Our data indicate that reconstitution of SCID mice with PBMC from EBV+ donors may constitute a useful model for determining the events involved in lymphomagenesis in humans, provided that strict control of all the experimental variables is guaranteed.