Mechanisms of tumor development were studied in SCID mice injected with human lymphoid cells from Epstein-Barr virus-positive (EBV+) donors. About 80% of peripheral blood mononuclear cell (PBMC)-injected animals developed a lymphoproliferative disease associated with oligoclonal EBV+ tumors of human B cell origin. No change in tumor development rate occurred when monocyte-depleted PBMC were inoculated. No tumors developed when purified B cells were injected. B cell lymphoproliferative disease was also prevented in most cases when PBMC-injected animals were treated with agents that prevent T cell activation, such as cyclosporin A. Both CD4+ and CD8+ T cell subpopulations were able to provide putative factor(s) necessary for EBV+ B cell expansion and progression to tumors. These data suggest that the transfer alone of potentially tumorigenic human cells into an immunodeficient environment, such as the SCID mouse, might not be sufficient for cell progression to tumor, and raise the possibility that chronic activation events could play a major role in the pathogenesis of some EBV+ lymphomas in the immunocompromised host.