IgD is thought to function primarily as an Ag receptor that is expressed, together with IgM, only on mature B lymphocytes. This differentiation stage-specific expression of IgD has been well characterized in mice, where δ mRNA is detected only in mature IgM/IgD B cells. Humans, in contrast to mice, have significant levels of serum IgD, suggesting that the regulation of this isotype might differ between the two species. Therefore, we examined the regulation of both IgM and IgD expression in cell lines encompassing the spectrum of human B lineage development. Surprisingly, two species of δ mRNA could be found at all differentiation stages- from μ+ pre-B cell to IgM-secreting plasmablast. These mRNA are translated to yield the membrane and secretory forms of δ. The membrane δ-chain: secretory δ-chain ratio did not necessarily reflect the membrane μ-chain:secretory μ-chain ratio in the same cell line, implying that different mechanisms are involved in the selection of membrane vs secretory μ- and δ-chains. The δ-chains synthesized in pre-B cells were degraded, but in more mature cell types IgD could be stably expressed and secreted. Exceptions to this panlineage synthesis of δ-chains were, however, observed in two of the B cell lymphomas, where δ expression was prevented by transcriptional and posttranscriptional mechanisms. The presence of δ-chain in pre-B cells and the secretion of IgD by more mature cells suggest that IgD may have immunoregulatory roles throughout B cell differentiation. These studies also indicated that the bias toward secretory μ-chain production that occurs in human IgM secreting cells results from posttranscriptional regulation. In addition, we have identified a B cell line that synthesizes both normal-sized μ-chains and those with smaller apparent m.w. translation products of truncated μ mRNA.