Reactive oxygen species (ROS), especially mitochondrial ROS, are postulated to play a significant role in muscle atrophy. We report a dramatic increase in mitochondrial ROS generation in three conditions associated with muscle atrophy: aging, in mice lacking CuZnSOD (Sod1^-/-), and in the neurodegenerative disease, Amyotrophic Lateral Sclerosis (ALS). Our data show ROS generation in muscle mitochondria is nearly 3-fold higher in 28- to 32-month-old than in 10-month-old mice, and is associated with a 30% loss in gastrocnemius mass. In Sod1^-/- mice, muscle mitochondrial ROS production is increased over 100% in 20 -month compared to 5-month-old mice along with a greater than 50% loss in muscle mass. ALS G93A mutant mice show a 75% loss of muscle mass during disease progression and up to 12-fold higher muscle mitochondrial ROS generation. In a second ALS mutant model, H46RH48Q mice, ROS production is ~4-fold higher than in control mice and is associated with a less dramatic loss (30%) in muscle mass. Thus, ROS production is strongly correlated with the extent of muscle atrophy in these models. Because each of the models of muscle atrophy studied here are associated to some degree with a loss of innervation, we were interested in determining if denervation plays a role in ROS generation in muscle mitochondria isolated from hind limb muscle following surgical sciatic nerve transection. Seven days post-denervation, muscle mitochondrial ROS production increased nearly 30-fold. We conclude that enhanced generation of mitochondrial ROS may be a common factor in the mechanism underlying denervation-induced atrophy