CYTOTOXIC CD4⁺ Thl-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 Thl-mediated cytotoxicity. Here we report that CD40-Iigand-stimuIated B cells were extremely sensitive, whereas anti-IgM-stimulated B cells were resistant, to Fas-mediated apoptosis. B cells stimulated by both CD40L and anti-IgM were not susceptible to cytolysis, demonstrating that anti-IgM-mediated protection is an active, dominant process. Resistance to Thl-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–2Kb (but not H–2K^d) spleno-cytes. 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.