Lubin et al recently described a new approach that enables the generation of human/mouse chimera by adoptive transfer of human peripheral blood mononuclear cells (PBMC) into lethally irradiated normal strains of mice, radioprotected with bone marrow (BM) from donors with severe combined immune deficiency (SCID). In the present study, we demonstrate in such human/mouse chimera a marked humoral response to recall antigen, such as tetanus toxoid (TT) or hepatitis B surface antigen (HBsAg), as well as a significant primary response to keyhole limpet hemocyanin (KLH). Maximal anti-KLH response in human/Balb chimera was attained 2 to 4 weeks after the immunization and declined thereafter. One week after transplantation, the predominant anti-KLH subtype was IgM, while after 2 weeks, the dominance had shifted to IgG. Similar primary antibody response was also demonstrated against the human immunodeficiency virus (HIV) Nef protein. Comparison between human/Balb and human/SCID chimera showed a major difference in their ability to mount a primary response against KLH. In Balb/c recipients, more than half of the mice exhibited marked IgM titers against KLH, while there was hardly any anti-KLH IgM response in the SCID recipients. From the earliest time point onwards, when anti-KLH antibodies were found in the latter chimera, they were predominantly of the IgG type. We have previously shown that in human/Balb chimera, unlike in SCID recipients, dissemination of transplanted PBMC into the spleen and other internal organs occurs within 24 hours. Therefore, it is likely that the early seeding in the appropriate microenvironment of the lymphoid tissues, is crucial for the maintenance of virgin human B cells.