Immunosuppression following severe sepsis remains a significant human health concern, as long-term survival rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to epigenetic suppression of IL-12 production by dendritic cells. However, the effect of severe sepsis on subsequent CD4+ T cell responses remains unclear. In the present study, CD4+ T cells from mice subject to an experimental model of severe sepsis (cecal ligation and puncture, CLP) were isolated and subjected to ex vivo restimulation. Naïve CD4+ T cells from CLP mice exhibited reduced proliferative capacity ex vivo and dysregulated cytokine production as compared to CD4+ T cells from sham surgery mice. Also, CD4+ T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing. Additionally, repressive histone methylation marks were evident at promoter regions for the TH1 cytokine interferon-γ (IFN-γ) and the TH2 transcription factor GATA-3 in naïve CD4+ T cells from CLP mice. These results provide evidence that naïve CD4+ T cells from postseptic mice are unable to properly commit to either the TH1 or TH2 lineage, possibly due to repressive histone methylation events associated with genes involved in cytokine production and gene transcription. This work was supported by NIH RO1 HL031237, HL074024, and T32 HL007517.