CYTOTOXIC CD4(+) Th1-cells induce cell death by triggering a Fas-dependent apoptotic pathway(1-6). Potential targets include activated B cells(3,7), but it is not known whether the mode of B-cell stimulation influences susceptibility to Th1-mediated cytotoxicity. Here we report that CD40-ligand-stimulated B cells were extremely sensitive, whereas anti-IgM-stimulated B cells were resistant, to Fas-mediated apoptosis, B cells stimulated by both CD4DL and anti-IgM were not susceptible to cytolysis, demonstrating that anti-IgM-mediated protection is an active, dominant process. Resistance to Th1-mediated cytotoxicity was similarly observed in CD40L-stimulated 3-83 (anti-H-2K(k,b))(8) transgenic B cells co-cultured with H-2K(k) or H-2K(b) (but not H-2K(d)) splenocytes, These results indicate that B cells can participate in regulating their own destruction. Protection against Fas-dependent apoptosis afforded by immunoglobulin-receptor engagement may constitute a fail-safe mechanism that eliminates bystander B cells activated by CD40L-expressing T cells, but ensures survival of antigen-specific B cells.