Adult spleen cells from C57BL.Ige mice, which generally are resistant to in vitro tolerance induction in the B-cell compartment, became hyporesponsive (tolerant) when cultured with antigen in the presence of an anti-allotype serum. Both antigen and anti-δ had to be present for this effect, which was hapten-specific and did not occur in C57BL/6 mice, which lack the Ig5-1 allotype of the δ-chain detected in this system. Preculture with anti-µ serum plus antigen, in contrast, did not cause tolerance induction in adult spleen B cells of either strain. These results suggest that the surface IgD may act as a failsafe receptor to prevent tolerance induction in adult B cells. Tolerance studies with spleen cells from mice with markedly reduced numbers of IgD+ve cells, because of a regimen of repeated injections of anti-δ serum beginning at birth δ-suppressed mice), confirmed the importance of membrane IgD in preventing tolerance, because such δ-suppressed mice were hypersusceptible to tolerance by antigen alone. Inasmuch as immature B cells lack IgD on their surface, these studies suggest that acquisition of IgD is an important maturational step in the ability of murine B cells to discriminate tolerogenic and immunogenic signals.