Primary murine splenic B cells are rendered sensitive or resistant to Fas-mediated apoptosis in a receptor-specific fashion. B cells stimulated though CD40 are Fas sensitive unless they also receive a signal though surface Ig that produces a state of resistance to Fas killing. Protection from Fas-mediated apoptosis takes time to develop and requires ongoing macromolecular synthesis; therefore, it appears to involve the induction and accumulation of one or more gene products. The role of Bcl-x was evaluated by examining the expression and function of this gene in primary B cells. bcl-x mRNA was induced by anti-IgM treatment of otherwise sensitive (CD40 ligand-treated) B cells. Bcl-x protein expression was induced by anti-IgM and appeared in a time frame that correlates well with the onset of anti-IgM-induced Fas resistance. Further, B cells from Bcl-x Tg mice were found to be resistant to Fas-mediated apoptosis. These results strongly suggest that the protection against Fas killing afforded by cross-linking surface Ig is mediated, at least in part, by an increase in Bcl-x.