The expression of CD95 (Fas/APO‐1) on B cells has been shown to play a direct role in their fate. B␣cells that chronically bind antigen due to prolonged antigen exposure, such as self‐reactive B cells, are induced to express CD95 by CD40 ligand (CD40L) and are subsequently eliminated by CD95 ligand (CD95L) when they present antigen to CD4⁺ T cells. B cells that bind antigen acutely due to sudden antigen encounter, such as foreign antigen reactive B cells, up‐regulate CD95, but are normally protected from CD95L‐mediated apoptosis. Here, however, it is shown in vivo that foreign antigen‐specific B cells fail to be protected from CD95‐dependent elimination in a host that is CD95 deficient, regardless of antigenic challenge. These data indicate that B cell antigen receptor (BCR)‐induced protection against CD95L‐mediated apoptosis is not absolute but depends upon other micro‐environmental factors in vivo. The normal balance between T cell‐dependent humoral immunity and tolerance is thus regulated intrinsically by CD95 expression on responding B cells, and extrinsically by CD95‐mediated control of CD95L or other molecules in the lymphoid micro‐environment.