A phase I dose escalation study was conducted with the human monoclonal anti-gp120 antibody F105, to evaluate the safety, pharmacokinetics, and functional activity of F105 in HIV-1-infected individuals. F105 is an IgG1(kappa) antibody reactive with a discontinuous epitope that overlaps the CD4-binding site of gp120. F105 neutralizes laboratory strains of HIV-1 and some primary isolates, and synergizes with other antibodies in neutralizing an expanded spectrum of isolates. Four patients each with CD4 counts between 200 and 500/mm3 received a single dose of F105 at 100 or 500 mg/m2, intravenously. Sustained levels of F105 were obtained in plasma, and there was no evidence of an immune response to F105 as determined by a double-antigen immunoassay. No patient experienced any toxicity. Infused antibody retained full functional activity as detected by the ability of sera to block the binding of labeled F105 to HIV-1-infected cells. Of note, all patients had preexisting antibody to the gp120 CD4-binding site. The ability to culture virus by quantitative microculture remained unchanged by this single dose of antibody. Thus, it can be concluded that F105 is safe and nontoxic as a single injection at the doses tested. Furthermore, the antibody retains full gp120-binding activity. In these patients, with preexisting CD4-binding site antibody, there is no evidence of anti-HIV-1 activity following a single antibody infusion.