Pathophysiological characteristics of hemorrhagic shock at high altitude are different from that at plain which involve severe injury, high mortality, difficult treatment and compromised liquid tolerance. High-altitude pulmonary/cerebral edema and multiple-organ dysfunction render the conventional treatment ineffective. Herein, we evaluated the resuscitation effects of hyperoxia solution on high-altitude hemorrhagic shock in rats. For this purpose, a rat model of high-altitude (3,658 m) hemorrhagic shock was established on the plateau and hyperoxia solution (4 ml/kg) was infused through external jugular vein for resuscitation at 60 min post-hemorrhage. Blood pressure, blood gas, left and right ventricular pressure, lung and brain water content, survival time, survival rate at 2 h, levels of inflammatory cytokines and free oxygen radicals in blood and tissue were determined. After resuscitation with hyperoxia solution, blood pressure, arterial oxygen partial pressure, left and right ventricular systolic pressure, ±dp/dt max, survival time and rate were significantly increased. Lung and brain water content were unchanged, malondialdehyde activity in lung, brain and plasma and levels of TNF-α, IL-1, IL-6, and endothelin were significantly decreased. Besides, CGRP was elevated with reduced injury and improved lung and kidney functions. Concludingly, resuscitation with hyperoxia solution is feasible and more effective than other classical liquids, making it the first choice of treatment for high-altitude hemorrhagic shock.