Despite previous attempts there is currently no suitable animal model available for xenogeneic graft versus host disease (XGVHD) mediated via human immunocompetent cells. Recently, we have developed an efficient protocol to engraft SCID mice with human peripheral blood lymphocytes (Hu-PBLs). The engraft-ment efficiency is extremely high, such that 100% of Hu-PBL-SCID mice die of XGVHD within 4 weeks after engraftment with Hu-PBLs (3-5 × l07 cells). A series of experiments was performed to investigate the mechanisms involved in the severe XGVHD. The results suggest that XGVHD was induced by human CD4+ T cells, antixenogeneic (antimouse) antibodies, and lympho-kines. The SCID mouse model will be extremely valuable for the evaluation and development of immunosuppressive agents and transplantation protocols for human XGVHD.