Duchenne Muscular Dystrophy (DMD), caused by loss of dystrophin is characterized by progressive muscle cell necrosis. However, the mechanisms leading to muscle degeneration in DMD are poorly understood. Here, we demonstrate that Stra13 protects muscle cells from oxidative damage, and its absence leads to muscle necrosis in response to injury in Stra13-deficient mice. Interestingly, Stra13-/- mutants express elevated levels of TNFalpha, reduced levels of heme-oxygenase-1, and display apparent signs of oxidative stress prior to muscle death. Moreover, Stra13-/- muscle cells exhibit an increased sensitivity to pro-oxidants, and conversely, Stra13 overexpression provides resistance to oxidative damage. Consistently, treatment with anti-oxidant N-acetylcysteine ameliorates muscle necrosis in Stra13-/- mice. We also demonstrate that Stra13 expression is elevated in muscles from dystrophin-deficient (mdx) mice, and mdx/Stra13-/- double mutants exhibit an early onset of muscle degeneration. Our studies underscore the importance of oxidative stress-mediated muscle degeneration in muscular dystrophy, and reveal the contribution of Stra13 in maintenance of muscle integrity.