We have previously reported the development of a two-step culture system in which soluble anti-mu monoclonal antibodies prime small resting murine B cells to secrete immunoglobulin (Ig) in response to restimulation with a mixture of interleukin-4 (IL-4) and IL-5. Here we have extended these studies to investigate the effects of engaging surface IgD (sIgD). We find that, unlike anti-mu, three different anti-delta monoclonal antibodies did not prime B cells to secrete Ig. In addition, these anti-delta antibodies inhibited anti-mu-stimulated priming for Ig secretion, while enhancing DNA synthesis in response to anti-mu. Furthermore, anti-delta antibodies still inhibited anti-mu-induced priming when added 24-48 h after anti-mu. These results therefore suggest that triggering of sIgD on B cells induces a dominant inhibitory signal which is not necessarily dependent upon co-ligation of sIgM and sIgD receptors. In addition, these findings raise the possibility that ligating sIgM or sIgD receptors on mature B cells in the absence of T cell help, may produce different downstream effects.