Background and objectives: The autophagy pathway has previously been suggested as an important protective factor in liver injury. The purpose of this study is to demonstrate the protective, autophagy-modulating effect of tri-iodothyronine (T3) on liver ischemia reperfusion injury. Methods: Liver ischemia reperfusion was induced in male C57BL/6 mice after T3 administration. Liver function, histological damage, inflammatory infiltration, cytokine production, oxidative stress, antioxidant capacity, autophagy changing, and autophagy-associated intracellular signaling pathway were assessed to evaluate the impact of antecedent T3 treatment on ischemia reperfusion induced liver injury. Results: After 70% liver ischemia reperfusion injury, mice that were preconditioned with appropriate T3 displayed significantly preserved liver function, less histological damage, less apoptosis, and enhanced antioxidant capacity. Further studies revealed that mice which were preconditioned with T3 before IR induction exhibited an increased level of autophagy mediated by MEK/ERK/mTORC1. Conclusions: Our results provide the first line of evidence indicating that antecedent T3 injection can provide protection for the liver against ischemia reperfusion induced injury by enhancing autophagy. Therefore, T3 preconditioning could be a potential therapeutic approach to prevent liver IR injury related to various clinical conditions. (C) 2015 Elsevier Inc. All rights reserved.