Replication of the IIIB strain of human immunodeficiency virus type 1 (HIV-1(IIIB)) in CB.17 scid/scid mice reconstituted with human peripheral blood lymphocytes (Hu-PBL-SCID) was investigated. Hu-PBL-SCID mice could be infected, in a dose-dependent manner, when HIV-1(IIIB) was injected intraperitoneally. Replication competent HIV-1 could be recovered from spleen, peripheral blood, bone marrow, thymus, lymph node, and peritoneal cavity, indicating the ability of the infection to spread to human tissue throughout the chimeric animals. HIV-1 infection was quantitated using p24 determination, end-point dilution culture, and polymerase chain reaction amplification. The level of HIV-1 replication in Hu-PBL-SCID mice was found to approximate the level reported in human infection. No HIV-1-specific immune response was generated to this infection, but nonspecific immune activation did occur, as also reported in human infection. Similarities therefore exist between HIV-1 infection of humans and Hu-PBL-SCID mice, which makes the latter an in vivo model in which to study HIV-1 replication.