The severe combined immunodeficient (SCID) mouse engrafted with human peripheral blood lymphocytes (PBLs) is a potentially useful model for the study of cancer immunotherapy. For this application, rapid, consistent, and high level engraftment of SCID mice with functional human cytotoxic effector cells is necessary. To date, short term human lymphoid cell engraftment in SCID mice has generally been low and variable. Further, most of the human cells detected within the first 30 days are found in the peritoneal cavity. The purpose of the present study was to improve short term reconstitution of human PBLs in the SCID mouse. When untreated SCID mice were injected with human PBLs, the mean level of CD3+ cells in the spleens was < 5% on days 6-32 after injection, as determined by flow cytometry (FCM). Depletion of SCID mouse natural killer (NK) cells with anti-asialo GM1 only marginally improved short term reconstitution with human CD3+ cells. Preirradiation of SCID mice with 3 Gy improved reconstitution to over 16% CD3+ cells on days 12-14 following engraftment. However, the combination of pretreatment with anti-asialo GM1 plus radiation, significantly increased the mean percentage of human CD3+ cells in the spleen to 40% within 2 weeks following injection of PBLs. Human T cells positive for CD4, CD8, TcR alpha beta, and TcR gamma delta, and human NK and B cells were detected in the spleens of irradiated plus anti-asialo GM1 pretreated SCID mice. The presence of human lymphoid cells was confirmed by immunohistologic staining. The human immune cells in these mice were shown to be functional by the in vivo demonstration of an appropriate secondary immune response to the injection of tetanus toxoid and by an in vivo proliferative response to phytohemagglutinin. Human NK cells could be found in the spleens and peripheral blood of irradiated plus anti-asialo GM1 pretreated mice. These cells were also shown to be competent by their ability to lyse the human NK sensitive tumor targets K562 and MOLT-4 in 51Cr release assays. Thus, pretreatment of SCID mice with radiation plus anti-asialo GM1 significantly improves short term human PBL engraftment and provides a potentially useful model for the study of cancer immunotherapy.