Interleukin-6 (IL-6) via its signal transducer gp130 is an important mediator of liver regeneration involved in protecting from LPS-induced liver injury after partial hepatectomy (PH). Here we generated mice either defective () in hepatocyte-specific gp130-dependent Ras or STAT activation to define their role during liver regeneration. Deletion of gp130-dependent signalling had major impact on acute phase gene (APG) regulation after PH. APG expression was blocked in gp130-STAT animals, while gp130-Ras mice showed an enhanced APG response and stronger SOCS3 regulation correlating with delayed hepatocyte proliferation. To define the role of SOCS3 during hepatocyte proliferation, primary hepatocytes were co-stimulated with IL-6 and HGF. Higher SOCS3 expression in gp130-Ras hepatocytes correlated with delayed hepatocyte proliferation. Next, we tested the impact of LPS - mimicking bacterial infection - on liver regeneration. LPS and PH induced SOCS3 in all animal strains and delayed cell cycle progression. Additionally, IL-6/gp130-dependent STAT3 activation in hepatocytes was essential in mediating protection and thus required for maximal proliferation. Unexpected, Oncostatin M was strongest induced in gp130-STAT animals after PH/LPS-induced stress and associated with hepatocyte proliferation in this strain. In summary, gp130-dependent STAT3 activation and concomitant SOCS3 during liver regeneration is involved in timing of DNA synthesis and protects hepatocyte proliferation during stress conditions.