The intermediate or "pre-progenitor" B-cell subpopulation giving primary adoptive responses has been found by this laboratory to be s-IgD-, whereas other laboratories have reported the progenitors of primary adoptive responses to be s-IgD+. This difference appears to depend on the recent history of environmental stimuli received by the mice. Deliberate administration of a complex non-specific stimulus, designed to mimic the effects of infection or certain types of experimental manipulation, shifted "pre-progenitor" activity from the s-IgD- compartment to the s-IgD+ compartment within 24 h. Neither horse erythrocytes (HRC) nor lipopolysaccharide (LPS) alone produced a reproducible effect, but the combination of HRC with low doses of LPS produced a marked shift to s-IgD+ activity. Some earlier experiments from this laboratory suggesting a striking effect with HRC alone probably resulted from suspension of HRC in saline contaminated by LPS-like material. Priming with HRC alone, under conditions which did not induce s-IgD, nevertheless stimulated the "pre-progenitors" to enter cell cycle. Three conclusions are drawn: (1) The stimulus for induction of s-IgD is not identical with the non-specific stimulus which selectively induces cell division in this intermediate B-cell subset; (2) the presence of IgD on the surface per se does not prevent the non-specific activation of these cells into division; (3) the absence of s-IgD is only a useful marker of the "pre-progenitor" subset if the mice are maintained under specific pathogen-free conditions and exogenous stimuli are controlled.