We have recently shown that lethally irradiated normal strains of mice, radioprotected with SCID bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). We now demonstrate that lethally irradiated Lewis rats can also be radioprotected with a transplant of SCID bone marrow cells, administered 1 day after total body irradiation. Split chimerism was found in PBMC, 30 days after transplantation, with predominance of SCID donor-type cells. The average percentages of CD4 and CD8 T cells, of mouse or rat origin, were < 1%. This chimerism status could be maintained for over 3 months. When human PBMC (300-1000 x 10(6) cells) were transplanted intraperitoneally 1 day after the administration of SCID bone marrow, prompt engraftment of human CD4 and human CD8 T cells, as well as human CD20 B cells, was found in the peritoneum and in internal organ (such as liver, lung, spleen, thymus, and lymph nodes). T cell activation was high: about 50% of the cells expressed HLA-DR and almost all expressed CD45RO. High titers of human Ig (> 1 mg/ml) were initially found after 2 weeks; these levels were similar to those found in the irradiated mouse model and in the SCID model. Likewise, marked human anti-tetanus response, predominantly of the IgG type, was recorded 2 weeks after the immunization, reaching maximal levels at 4 weeks. The triple-chimeric SCID-like rats, which accept as much as 1000 x 10(6) human PBMC, can potentially be used to elicit both antibody responses and T cell responses against specific antigens, with the advantages of a larger animal.