The low levels of serum IgD found in mice and the lack of a typical DNA switch sequence between Cδ and Cμ raise the possibility that the generation of murine IgD-secreting cells results from a chance 'mistake' rather than a controlled process. The recent observation that injection of mice with purified IgD upregulates IgD receptor expression on helper T cells and enhances the ability of these T cells to induce B cells to differentiate into antibody secreting cells led us to look for evidence of controlled differentiation of B cells into IgD-secreting cells. To do this, we injected mice with a goat antibody to IgD (GaMδ), because this antibody stimulates large increases in IgM, IgG1, IgG2a, and IgE secretion. Mice injected with GaMδ demonstrated a large increase in splenic content of mRNA specific for the secreted form of δ-chain, as well as a greater than 100-fold increase in the percentage of splenic IgD-containing plasmablasts. The secretory IgD response was totally T-dependent. Production of the secretory form of IgD was not seen until 7 days after GaMδ injection, and peaked sharply on day 8, whereas by day 6 IgM secretion had already peaked and IgG1 and IgG2 secrtion had attained substantial levels. This observation suggests that: 1) either cells that synthesize large quantitites of the secretory form of δ-chain, unlike cells that synthesize large quantitites of the secretory forms of γ-, ε-, or α-chains, do this without deleting Cμ or, despite the absence of a typical DNA switch sequence between Cμ and Cδ, controls must exist to effect the Cμ deletion and VDJ-Cδ joining; and 2) if secreted IgD has a role in the regulation of a humoral immune response it most likely is involved in later processes, such as memory cell generation or response termination, rather than in relatively early processes, such as helper T cell activation.