What is the central question of this study? Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) gene transfer as a treatment for Duchenne muscular dystrophy is efficacious even with advanced disease. What is the main finding and its importance? PGC-1α pathway activation strategies may be most effective when initiated at the earliest possible time. Duchenne muscular dystrophy is a progressive and fatal muscle wasting disease caused by a dystrophin deficiency. We previously found that gene transfer of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) increased abundance of utrophin and increased mitochondrial biogenesis using prevention and rescue treatment protocols. Our purpose in this investigation was to determine the extent to which PGC-1α gene transfer would rescue dystrophic muscle following prolonged disease progression. One-year-old mdx mice from our colony were injected in one hindlimb with a virus driving expression of PGC-1α, while the contralateral limb was injected with empty capsid. Three months after viral gene transfer, PGC-1α expression was 40-fold greater than in contralateral limbs. Specific tension was increased by ∼ 60% (P < 0.05), and force produced during the final contraction of a fatigue protocol was 60% greater in treated soleus muscles compared with contralateral control muscles (P < 0.05). Histopathology was not improved by PGC-1α overexpression. Also, while there were numerous differences in gene expression between healthy and dystrophic muscle, there were relatively few differences between PGC-1α-treated limbs and contralateral control limbs. These data indicate that PGC-1α pathway activation may interrupt the disease process even if initiated within the context of advanced disease; however, the mechanism that underlies this functional correction is not apparent.