OBJECTIVE To determine whether passive transfer of a monoclonal antibody specific for the principal neutralizing determinant in the V3 region of HIV-1IIIB gp120 can protect mice with severe combined immunodeficiency (SCID) transplanted with normal human peripheral blood leukocytes (hu-PBL), designated hu-PBL-SCID mice, from subsequent challenge with the homologous viral strain. METHODS hu-PBL-SCID mice were given intraperitoneal injections of an anti-HIV-1 neutralizing murine monoclonal antibody (BAT123), its mouse-human chimeric form (CGP 47 439), or a control murine antibody (PNTU), at a dose of 40 mg/kg. The mice were then challenged intraperitoneally with 10 mouse infectious doses of HIV-1IIIB. Three weeks later the mice were killed, and spleen cells and peritoneal lavage collected for determination of infection by coculture for viral isolation and by detection of HIV-1 DNA using polymerase chain reaction (PCR). RESULTS All three antibodies had similar serum half-lives of 9-12 days. No toxicity was observed in the animals. HIV-1 was recovered by coculture from five out of the six mice given PNTU, and by PCR from two out of the six mice given PNTU, but was not recovered by either technique from any of the 12 mice given BAT123 or CGP 47 439. CONCLUSIONS BAT123 and CGP 47 439, which are specific for the principal neutralizing determinant of HIV-1IIIB, protect hu-PBL-SCID mice from infection by this viral strain. Our findings support the use of the hu-PBL-SCID mouse as an in vivo model for studying protection against HIV-1 infection by passive immunization with anti-HIV-1 neutralizing antibodies.