It has been shown that engraftment of human peripheral blood lymphocytes (PBL) from Epstein-Barr virus (EBV) seropositive donors in C.B-17/SCID mice is associated with a high incidence of human B cell tumors. More recently, we described a new approach enabling engraftment of human PBL in normal strains of mice or rats receiving lethal split-dose radiation and radioprotected with SCID bone marrow. We now demonstrate that, in contrast to SCID recipients of human PBL, Balb/c and C3H/HeJ recipients of 50-100 x 10(6) human PBL did not develop any EBV lymphoma during a 7-month follow-up period, but were successfully engrafted with human B and T cells. On the other hand, lymphoma developed in 90% of the C.B-17/SCID mice infused with 70 x 10(6) human PBL from the same donor. Likewise, 36% of beige/nude/xid (BNX) mice, exposed to 12 Gy TBI, radioprotected with SCID bone marrow and then transplanted with human PBL developed lymphoma. Similar results were obtained when different strains were infused with PBL of the same donor. Immunohistochemical analysis indicated that the tumor cells were of human B cell origin and expressed the EBV-encoded latent membrane protein-1 and nuclear antigen 2. While further studies are required to understand the mechanisms which suppressed outgrowth of EBV lymphoma in human --> mouse radiation chimera, compared to human --> C.B-17/SCID or human --> BNX chimera, this marked resistance offers new possibilities for transplantation of hematopoietic tissues or cells from EBV-positive donors.