Our laboratory has reported that mice deficient in Programmed Cell Death Receptor (PD-1) have increased bacterial clearance and improved survival in experimental sepsis induced by cecal ligation and puncture (CLP). In response to infection, the liver clears the blood of bacteria and produces cytokines. Kupffer cells (KC), the resident macrophages in the liver, are strategically situated to perform the above functions. However, it is not known if PD-1 expression on KCs is altered by septic stimuli, let alone if PD-1 ligation contributes to the altered microbial handling seen. Here we report that PD-1 is significantly up-regulated on KCs during sepsis. PD-1 deficient septic KCs displayed markedly enhanced phagocytosis and restoration of the expression of MHCII and CD86, but reduced CD80 expression when compared with septic wild type (WT) mouse KCs. In response to ex vivo LPS stimulation, the cytokine productive capacity of KCs derived from PD-1-/- CLP mice exhibited a marked, albeit partial, restoration of the release of IL-6, IL-12, IL-1β, MCP-1 and IL-10 when compared with septic WT mouse KCs. In addition, PD-1 gene deficiency decreased LPS-induced apoptosis of septic KCs, as indicated by decreased levels of cleaved caspase-3 and reduced TUNEL-positive cells. Exploring the signal pathways involved, we found that after ex vivo LPS stimulation, septic PD-1-/- mouse KCs exhibited an increased Akt phosphorylation and a reduced p38 phosphorylation in comparison to septic WT mouse KCs. Together, these results indicate that PD-1 appears to play an important role in regulating the development of KC dysfunction seen in sepsis.