Intraorgan dendritic cells (DCs) monitor the environment and help translate triggers of innate immunity into adaptive immune responses. Liver‐based DCs are continually exposed, via gut‐derived portal venous blood, to potential antigens and bacterial products that can trigger innate immunity. However, somehow the liver avoids a state of perpetual inflammation and protects central immune organs from overstimulation. In this study, we tested the hypothesis that hepatic interleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 (STAT3) activity increases the activation/maturation threshold of hepatic DCs toward innate immune signals. The results show that the liver nuclear STAT3 activity is significantly higher than that of other organs and is IL‐6–dependent. Hepatic DCs in normal IL‐6 wild‐type (IL‐6^+/+) mice are phenotypically and functionally less mature than DCs from IL‐6–deficient (IL‐6^−/−) or STAT3‐inhibited IL‐6^+/+ mice, as determined by surface marker expression, proinflammatory cytokine secretion, and allogeneic T‐cell stimulation. IL‐6^+/+ liver DCs produce IL‐6 in response to exposure to lipopolysaccharide (LPS) and cytidine phosphate guanosine oligonucleotides (CpG) but are resistant to maturation compared with IL‐6^−/− liver DCs. Conversely, exogenous IL‐6 inhibits LPS‐induced IL‐6^−/− liver DC maturation. IL‐6/STAT3 signaling influences the liver DC expression of toll‐like receptor 9 and IL‐1 receptor associated kinase‐M. The depletion of gut commensal bacteria in IL‐6^+/+ mice with oral antibiotics decreased portal blood endotoxin levels, lowered the expression of IL‐6 and phospho‐STAT3, and significantly increased liver DC maturation. Conclusion: Gut‐derived bacterial products, by stimulating hepatic IL‐6/STAT3 signaling, inhibit hepatic DC activation/maturation and thereby elevate the threshold needed for translating triggers of innate immunity into adaptive immune responses. Manipulating gut bacteria may therefore be an effective strategy for altering intrahepatic immune responses. (HEPATOLOGY 2007.)