Objectives: Crush syndrome (CS) is characterized by a systemic manifestation of traumatic rhabdomyolysis, leading to multiple organ dysfunction and death. Ischemia-reperfusion (IR) injury is commonly responsible for systemic response. Extending studies have shown that hydrogen gas treatment ameliorated IR injury in numerous experimental models; however, its effect on CS has not been well examined. This study aimed to investigate the effects of hydrogen gas inhalation following crush injury in an experimental model of CS. Methods: Male Sprague-Dawley rats were subjected to experimental CS by applying a total of 3.0 kg weight to both hindlimb under general anesthesia for 6 h. Immediately after decompression, the animals were randomly placed in a gas chamber filled with either air or 1.3% hydrogen gas. Animals were sacrificed 18 h or 24 h following gas exposure for non-survival studies or for survival study, respectively. Results: The rats with hydrogen treatment (n = 6) had a higher 24-h survival than the rats with air treatment (n = 9) (100% vs. 44%, p = 0.035). Lactate concentrations (2.9 ± 0.2 vs. 2.2 ± 0.2 mmol/L, p = 0.040) and creatine kinase (34,178 ± 13,580 vs. 5005 ± 842 IU/L, p = 0.016) were lower in the hydrogen group compared with the air group 18 h after decompression (n = 4 in the air group, and n = 5 in the H2 group). Histological analysis revealed that the damage to the rectus femoris muscle and kidney appeared to be ameliorated by hydrogen treatment. Conclusion: Hydrogen gas inhalation may be a promising therapeutic approach in the treatment of CS. [ABSTRACT FROM AUTHOR]