Immunization with IgG/Ag or IgE/Ag complexes leads to a higher production of specific Abs than immunization with Ag alone. The enhancing effect of IgE is exclusively dependent upon the low-affinity receptor for IgE, FcεRII, whereas the mechanism behind IgG-mediated enhancement is unknown. We have investigated whether receptors for the Fc part of IgG are required for responses to IgG/Ag. Mice lacking the γ subunit of Fc receptors (FcRs)(FcRγ−/−), FcγRII (FcγRII−/−), or FcγRIII (FcγRIII−/−) were immunized with BSA-2, 4, 6-trinitrophenyl (TNP) alone or BSA-TNP complexed to monoclonal TNP-specific IgG1, IgG2a, or IgG2b. As expected, all subclasses enhanced the Ab-response to BSA in wild-type mice. Enhancement was in the same order of magnitude in FcγRIII−/− mice (≤ 177-fold of controls administered Ag alone), whereas it was abrogated in FcRγ−/− mice and augmented in FcγRII−/− mice (≤ 5147-fold of controls). The response to IgE/Ag complexes in FcRγ−/− and FcγRII−/− mice was similar to that seen for wild-type mice, demonstrating that non-FcγR-dependent responses were normal. Our observations suggest that IgG/Ag complexes enhance Ab responses via FcγRs. Moreover, they reveal a strong negative regulation of Ab responses to IgG/Ag exerted by FcγRII.