I ncreasing evidence demonstrates that IL-6 has a protective role during liver injury. IL-6 activates intracellular pathways via the gp130 receptor. In order to identify IL-6–gp130 pathways involved in mediating liver protection, we analyzed hepatocyte-specific gp130 knockout mice in a concanavalin A–induced (Con A–induced) model of immune-mediated hepatitis. We demonstrated that IL-6–gp130–dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A–induced hepatitis. gp130-STAT3 signaling in hepatocytes mediates the IL-6–triggered protective effect. This was demonstrated by analysis of IL-6–induced protection in mice selectively deficient for gp130-dependent STAT1/3 or gp130-SHP2-RAS signaling in hepatocytes. To identify IL-6–gp130–STAT1/3 dependently expressed liver-protective factors, we performed gene array analysis of hepatic gene expression in hepatocyte-specific gp130^–/– mice as well as in gp130-STAT1/3– and gp130-SHP2-RAS-MAPK–deficient mice. The mouse IL-8 ortholog KC (also known as Gro-α) and serum amyloid A2 (SAA2) was identified as differentially IL-6–gp130–STAT3–regulated genes. Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A–induced hepatitis. In summary, this study defines IL-6–gp130–STAT3–dependent gene expression in hepatocytes that mediates IL-6–triggered protection in immune-mediated Con A–induced hepatitis. Additionally, we identified the IL-6–gp130–STAT3–dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases.