Gp130-mediated IL-6 signaling may play a role in oval cell proliferation in vivo. Levels of IL-6 are elevated in livers of mice treated with a choline-deficient ethionine-supplemented (CDE) diet that induces oval cells, and there is a reduction of oval cells in IL-6 knockout mice. The CDE diet recapitulates characteristics of chronic liver injury in humans. In this study, we determined the impact of IL-6 signaling on oval cell-mediated liver regeneration in vivo. Signaling pathways downstream of gp130 activation were also dissected. Numbers of A6+ve liver progenitor oval cells (LPCs) in CDE-treated murine liver were detected by immunohistochemistry and quantified. Levels of oval cell migration and proliferation were compared in CDE-treated mouse strains that depict models of gp130-mediated hyperactive ERK-1/2 signaling (gp130ΔSTAT), hyperactive STAT-3 signaling (gp130Y757F and Socs-3−/ΔAlb) or active ERK-1/2 as well as active STAT-3 signaling (wild-type). The A6+ve LPC numbers were increased with IL-6 treatment in vivo. The gp130Y757F mice displayed increased A6+ve LPCs numbers compared with wild-type and gp130ΔSTAT mice. Numbers of A6+ve LPCs were also increased in the livers of CDE treated Socs-3−/ΔAlbmice compared with their control counterparts. Lastly, inhibition of ERK-1/2 activation in cultured oval cells increased hyper IL-6-induced cell growth. For the first time, we have dissected the gp130-mediated signaling pathways, which influence liver progenitor oval cell proliferation. Conclusion: Hyperactive STAT-3 signaling results in enhanced oval cell numbers, whereas ERK-1/2 activation suppresses oval cell proliferation. (HEPATOLOGY 2007;45:486–494.)