Inbred C.B-17-scid/scid mice accept human peripheral blood mononuclear cell (PBMC) xenografts and are susceptible to human immunodeficiency virus type 1 (HIV-1) infection, but low levels of PBMC engraftment impede use of this system in HIV research. This report describes the effect of host strain background on human PBMC engraftment and HIV infectivity in scid mice. Back-crossing the scid mutation to the NOD/Lt strain (designated NOD/LtSz-scid/scid) increased the percentage of engrafted human PBMC in recipient spleens by 5- to 10-fold compared with that in C.B-17-scid/scid stock. Four weeks after human PBMC-injected mice were infected with HIV-1, 79% of NOD/LtSz-scid/scid spleens harbored replicating virus compared with only 39% of spleens in C.B-17-scid/scid mice. The NOD/LtSz-scid/scid mouse may provide a useful small animal model for studies of HIV-1.