The inhibitory effect on antibody production by immune complexes has been shown to depend on co-ligation of the B-cell antigen receptor (BCR) with the low-affinity receptor for immunoglobulin G (IgG) (Fc gammaRIIb, CD32). Here we report that immunoglobulin E (IgE) synthesis, induced in a BCR-independent manner by interleukin-4 (IL-4) and anti-CD40 antibody, was inhibited by CD32 ligation. The observed effect was specific for CD32 as, first, antibodies directed against other B-cell surface structures had no inhibitory effect, and, second, treatment with anti-CD32 of cells that had been in culture for 2 days was ineffective owing to the down-regulation of CD32 expression. IgE inhibition was also observed in cells stimulated by IL-4/CD40 F(ab')(2) or IL-4 plus soluble CD40 ligand, demonstrating that co-cross-linking of CD32 and CD40 was not necessary to induce inhibition. Mechanistic studies into the IgE class switch process demonstrated that IL-4/anti-CD40-induced IgE germline gene transcription and B-cell proliferation were not affected by CD32 ligation. The data demonstrate that the negative regulatory role of the CD32 molecule is not restricted to BCR-induced B-cell activation, but is also functional on other B-cell activation pathways mediated by CD40 and IL-4.