Human anti-IgE autoantibodies have been identified and implicated in the regulation of IgE-mediated reactions and IgE synthesis. In order to study the potential regulatory role of anti-IgE antibodies on IgE binding to the FcεRII we used a panel of IgE-specific monoclonal antibodies that were mapped by Western blotting against a series of recombinant ε domain peptides. Antibodies specific for all ε domains were detected except those against CεHl. Using a competitive inhibition cell-binding assay on FcεRII + 8866 cells, we identified two major patterns of anti-IgE activity. Antibodies specific for the CεH3 domain removed IgE whereas those specific for the CεH2 domain enhanced IgE binding to the FcεRII. The anti-CεH2 antibodies, in contrast to the anti-CεFD antibodies, could not dissociate cell-bound IgE from the FcεRII. Using preformed immune complexes of IgE and anti-IgE antibodies, it was clear that the anti-CεH2 antibodies bound more IgE to the FcεRII by addition of immune complexes to the cell surface. Our results suggest that the opposing actions of either inhibition or enhancement of IgE binding by anti-IgE antibodies are related to their ε domain specificity.