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Ischemia-reperfusion injury is one of the leading causes of tissue damage and dysfunction, in particular, free tissue transfer, traumatically amputated extremity, and prolonged tourniquet application during extremity surgery. In this study, the authors investigated the therapeutic effects of hydrogen gas on skeletal muscle ischemia-reperfusion injury.The authors compared the concentration of hydrogen in a muscle on intraperitoneal administration of hydrogen-rich saline and on inhalation of hydrogen gas. Animals were subjected to ischemia-reperfusion. Mice were treated with inhalation of hydrogen gas, and the hind gastrocnemius muscle was collected. Muscle morphology and inflammatory change were evaluated after ischemia-reperfusion. Moreover, a footprint test was performed to assess the functional effect of hydrogen.Hydrogen concentration of tissue was significantly higher, and the elevated level was maintained longer by hydrogen gas inhalation than by intraperitoneal administration of hydrogen-rich saline. Infarct zone and area with loss of tissue structure and marked cellular infiltration were significantly decreased in groups treated by hydrogen gas inhalation during ischemia-reperfusion; however, these effects were not observed by posttreatment of hydrogen. One week after ischemia-reperfusion, mice that had been pretreated with hydrogen gas recovered faster and achieved smoother walking in appearance compared with mice in the other groups as assessed by the footprint test.Inhalation of hydrogen gas attenuates muscle damage, inhibits inflammatory response, and enhances functional recovery. These findings suggest that the optimal route for hydrogen delivery is continuous inhalation of hydrogen gas, which could be a novel clinical mode of treatment in ischemia-reperfusion injury.