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In addition to its pro-apoptotic function in the death receptor pathway, roles for caspase-8 in mediating T-cell proliferation, maintaining lymphocyte homeostasis, and suppressing immunodeficiency have become evident. Humans with a germline point mutation of CASPASE-8 have multiple defects in T cells, B cells, and NK cells, most notably attenuated activation and immunodeficiency. By generating mice with B-cell-specific inactivation of caspase-8 (bcasp8^-/-), we show that caspase-8 is dispensable for B-cell development, but its loss in B cells results in attenuated antibody production upon in vivo viral infection. We also report an important role for caspase-8 in maintaining B-cell survival following stimulation of the Toll-like receptor (TLR)2, -3, and -4. In response to TLR4 stimulation, caspase-8 is recruited to a complex containing IKKαβ, and its loss resulted in delayed NFκB nuclear translocation and impaired NFκB …