Sepsis induces extensive lymphocyte apoptosis that contributes to immunosuppression and mortality. Activation of the canonical NF-κB pathway, however, prevents TNF-α–induced lymphocyte apoptosis. In this study the function of canonical NF-κB in T cells was studied in the context of murine sepsis. Upon cecal ligation and puncture (CLP), NF-κB DNA binding activity in thymocytes declines relative to sham-operated mice. This decline in NF-κB activity is most likely due to posttranslational modifications such as deacetylation of p65. In parallel, cleavage of procaspase-3 is increased, whereas expression of NF-κB-dependent antiapoptotic genes Bcl-xL and c-IAP2 is suppressed upon sepsis induction. Interestingly, adoptive transfer of IκBα-deficient fetal liver stem cells into sublethally irradiated lymphopenic host mice reduced the decline in thymocyte survival, increased peripheral T cell numbers, and improved the mortality rate relative to wild-type reconstituted hosts after cecal ligation and puncture. In conclusion, lymphocyte-directed augmentation of canonical NF-κB ameliorates immunosuppression during murine sepsis. These data provide evidence for a new approach in sepsis therapy.