Cytochrome c oxidase (COX) deficiency， one of the most common respiratory-chain defects in humans， has been associated with mutations in either mitochondrial DNA genes or nucleus-encoded proteins that are not part in but promote the biogenesis of COX. Mutations of nucleus-encoded structural subunits were sought for but never found in COX-defective patients， leading to the conjecture that they may be incompatible with extra-uterine survival. We report a disease-associated mutation in one such subunit， COX6B1. Nuclear-encoded COX genes should be reconsidered and included in the diagnostic mutational screening of human disorders related to COX deficiency.