We have studied the expression and function of Fas antigen on murine B lymphocytes. While Fas was present on only a few B cells in the bone marrow, spleen, lymph node or peripheral blood, its expression could be strongly up‐regulated by stimulation with soluble CD40 ligand (CD40L). Treatment with anti‐IgM and interleukin‐4 (IL‐4) alone did not induce significant Fas expression but enhanced CD40L‐mediated up‐regulation of Fas expression. The T cell‐derived signal via CD40 is therefore a potent inducer of Fas expression by B lymphocytes. The sensitivity to Fas‐mediated apoptosis was found to depend on the duration of B cell activation. B cells activated for 1 day were resistant to Fas‐mediated cell death, whereas B cells activated for 3 days were relatively sensitive. Interestingly, different sensitivity to Fas‐mediated death signal was observed in 2‐day activated B cells. It was found that B cells stimulated with CD40 L alone were more sensitive to Fas‐mediated apoptosis than were cells stimulated with CD40L plus anti‐IgM or IL‐4, and in particular, the combination of the two. The greater sensitivity exhibited by B cells stimulated with CD40L alone seems to be related to limited activation of these cells in the absence of additional stimulation. Co‐stimulation of B cells in the presence of CD40L and anti‐Fas antibody resulted initially in activation of B lymphocytes, as reflected by the expression of activation markers and cell growth, but this was followed by growth inhibition and cell death. The data demonstrate that the B cell response can be regulated positively and negatively by signaling through CD40 and Fas antigens, respectively.