Cross-linking of surface IgM by anti-IgM antibody caused activation-induced cell death of a surface IgM⁺, IgD⁺ human B lymphoma cell line, B104. The dying B104 cells did not show the morphology of apoptosis but did show that of necrosis. However, anti-IgM antibody caused apoptosis of another surface IgM⁺, IgD⁺ human B lymphoma cell line, DND-39. The influx of extracellular Ca²⁺ was necessary for the cell deaths of B104 and DND-39 caused by anti-IgM antibody. Their cell deaths were inhibited by cyclosporine. The anti-IgM antibody-induced cell death of DND-39, but not that of B104, was prevented by costimulation with anti-CD40 antibody. In human peripheral blood B-cells, anti-IgM antibody inhibited cell cycle transition induced by Staphylococcus aureus Cowan I at the G2/M interphase without inhibition of DNA synthesis. In this system, too, anti-CD40 antibody canceled the inhibitory signal transduced through surface IgM and increased the number of M phase cells. Blocking antibodies against the leukocyte function-associated antigen-1/intercellular adhesion molecule-1 system decreased the rescue effect of anti-CD40 antibody in both DND-39 cells and peripheral B-cells, which shows that leukocyte function-associated antigen-1/intercellular adhesion molecule-1-dependent cell adhesion plays an important role in the CD40-mediated inhibition of surface IgM-mediated negative signals. (J ALLERGY CLIN IMMUNOL 1995;96:1136-44.)