To improve the engraftment of human peripheral blood lymphocytes (PBL) to severe combined immunodeficient (SCID) mice, and to elucidate the factors which prevent the PBL's survival, we treated SCID mice with mAb, which neutralizes murine IFN-gamma's ability to activate cell-mediated immunity. Compared with untreated mice, mAb-treated mice retained significantly higher numbers and ratios of human PBL in the peritoneal cavity and spleen, as well as significantly higher serum titers of human IgG and IgM. Histologically, host versus graft reaction (HVGR) was less severe in the mAb-treated mice. Moreover, these phenomena were completely abrogated when mice were also treated with murine recombinant IFN-gamma. These results suggest that murine IFN-gamma plays an important role in the rejection of human cells in SCID mice and that its depletion by means of mAb treatment can significantly reduce HVGR and improve the engraftment of human PBL.