Growth arrest–specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here we report an early increase in serum GAS6 levels after I/R exposure. Moreover, unlike wild‐type (WT) mice, Gas6^−/− mice were highly sensitive to partial hepatic I/R, with 90% of the mice dying within 12 hours of reperfusion because of massive hepatocellular injury. I/R induced early hepatic protein kinase B (AKT) phosphorylation in WT mice but not in Gas6^−/− mice without significant changes in c‐Jun N‐terminal kinase phosphorylation or nuclear factor kappa B translocation, whereas hepatic interleukin‐1β (IL‐1β) and tumor necrosis factor (TNF) messenger RNA levels were higher in Gas6^−/− mice versus WT mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes and thus protected them from hypoxia‐induced cell death, whereas GAS6 diminished lipopolysaccharide‐induced cytokine expression (IL‐1β and TNF) in murine macrophages. Finally, recombinant GAS6 treatment in vivo not only rescued GAS6 knockout mice from severe I/R‐induced liver damage but also attenuated hepatic damage in WT mice after I/R. Conclusion: Our data have revealed GAS6 to be a new player in liver I/R injury that is emerging as a potential therapeutic target for reducing postischemic hepatic damage. (HEPATOLOGY 2010;)