Here we used an adeno-associated virus (AAV) vector to deliver human NDUFS4 (hNDUFS4) in Ndufs4−/− mice and test proof-of-principle feasibility and efficacy of a gene therapy strategy aimed to ameliorate the clinical and biochemical phenotype of an otherwise fatal mitochondrial encephalomyopathy. The gene discussed is NDUFS4; the disease is mitochondrial encephalomyopathy.