Apoptosis of CD4⁺ T cells and T_H2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell–dependent IgM and IgG_2a antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4⁺ T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3ζ. Five days following immunization, CD4⁺ T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-γ but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4⁺ T-cell proliferation, increased T_H1 and T_H2 cytokine production, partially prevented CD3ζ down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4⁺ T cells but not CD25⁺ regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4⁺ T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.