Abstract: To examine the effect of HIF-1α on Nrf2-ARE antioxidant pathway in mice skeletal muscle after acute exhaustion exercise. Methods: HIF-1α high expression (H) and C57 BL/6 J mice (W) were used at 20 respectively and each kind of mice were randomly divided into two groups: control (C) and exercise (E) . The treadmill exercise was preformed at the acute exhaustion exercise. On the day of acute exercise, mice allocated to perform treadmill running were subject to 5% incline and 5 min at 10 m/min, and then increased 3 m/min every 3 minutes. Mice were sacrificed at the indicated time points following treadmill running.Nrf2, phosphor-Nrf2 (Ser40) , nuclear Nrf2 protein were measured by Western Blot and Nrf2-ARE binding activity, the mRNA and proetin levels of Nrf2 target genes, key antioxidant enzymes (SOD1, SOD2, CAT, NQO-1) and ROS level, were also measured in skeletal muscles after the interventions. Results: 1) The results showed that compared with WC, RNA and protein expression level of Nrf2 were increased in HC skeletal muscles. Nrf2-ARE binding activity, Nrf2 target gene SOD1, SOD2, NQO-1 m RNA expression and NQO-1 protein expression were also increased in HC skeletal muscles. Meanwhile, ROS level in HC skeletal muscles decreased significantly. 2) After the acute exhaustion exercise, high HIF-1α expression mice (HE) had higher expression of p-Nrf2 (Ser40) and nuclear Nrf2 protein than the wide type mice (WE) . The m RNA expression of SOD1 and m RNA/protein of NQO-1 in HE increased as well. In contrast, ROS level decreased significantly in HE muscles. Conclusion: The result indicated that the proper high expression of HIF-1α could promote the antioxidant capacity of skeletal muscle in mice through Nrf2-ARE pathway.