Activation of human B cells in vitro either by cross‐linking of surface immunoglobulins (sIg) or by triggering CD40 antigen, in the presence of interleukin‐10 (IL‐10) and interleukin‐2 (IL‐2), may result in high levels of immunoglobulin secretion in vitro. We studied the combined effects of ligation of the B‐cell receptor (BCR) and CD40 [ with anti‐CD40 monoclonal antibody (mAb)] on B‐cell proliferation and production of human immunoglobulin. For this purpose highly purified splenic B cells were cultured with various combinations of anti‐CD40 and IL‐10/IL‐2 or IL‐4 in the presence of CD32‐transfected L cells. Simultaneous cross‐linking of the BCR was achieved by mAb held on CD32–L cells or Staphylococcus aureus (SA). We found that dual BCR and CD40 ligation with IL‐10/IL‐2 leads to reduced immunoglobulin G (IgG) secretion compared with B cells stimulated with either anti‐CD40 and IL‐10/IL‐2, or compared with B cells stimulated with SA or anti‐BCR mAb and IL‐10/IL‐2. Dual BCR and CD40 ligation with anti‐immunoglobulin mAb (anti‐κ+anti‐λ light chains) but not with SA induced a similar reduction in IgM production. The reduced immunoglobulin secretion found during dual ligation is accompanied by increased proliferation. This was independent of cytokine stimulation but SA/CD40‐induced proliferation was increased in the presence of IL‐10/IL‐2, although not with IL‐4. The combination anti‐κ and anti‐λ with anti‐CD40 showed a long‐term suppression of IgG and IgM production (at least 14 days), while anti‐κ or anti‐λ alone, or SA, allowed a moderate recovery of immunoglobulin production by day 14. These results suggest that simultaneous B‐cell antigen receptor cross‐linking and CD40 engagement via CD40L on T cells induces strong initial proliferation. This may be followed later by antibody production depending on the strength of the BCR signal and the presence of the appropriate cytokines.