The ability of antigen-specific IgE antibodies to modulate the in vivo antibody response was studied by comparing the antibody response in mice immunized with 2,4,6-trinitrophenyl (TNP)-specific monoclonal IgE followed by bovine serum albumin (BSA)-TNP or with BSA-TNP alone. The serum IgG antibody response against BSA, measured in enzyme-linked immunosorbent assay ELISA, was enhanced up to 100-fold in groups receiving IgE. The enhancement required specific interaction between IgE and antigen, since no effect was seen when unconjugated BSA was used as antigen. Polyclonal activation by IgE/antigen complexes did not occur. IgE given 24 h after specific antigen had no stimulatory capacity. Pretreatment of the mice with Fc epsilon receptor type II (Fc epsilon RII)-specific monoclonal antibody completely inhibited the IgE-mediated enhancement. Thus, the data demonstrate for the first time an in vivo role for Fc epsilon RII in enhancement of specific antibody production.