Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1) is a principal regulator of mitochondrial biogenesis and oxidative metabolism. Results: In this study, we examined whether PGC-1 plays a protective role in ALS by using a double transgenic mouse model where PGC-1 is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1). Our results indicate that PGC-1 significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord. Conclusion: Our results demonstrate that PGC-1 plays a beneficial role in a mouse model of ALS, suggesting that PGC-1 may be a potential therapeutic target for ALS therapy.