We report two sisters (32 and 36 years old) with familial deaf-mutism, progressive external ophthalmoplegia, leukodystrophy and mitochondrial myopathy. T2-weighted brain MRI demonstrated diffuse symmetrical high intensity areas in the white matter. Their muscle biopsies showed ragged-red fibers and cytochrome c oxidase (CCO)-negative fibers. CCO activity in biopsied muscle decreased to about 20% of normal control. They had no deletions of the mitochondrial DNA and no point mutations in mitochondrial tRNA. Their brother was diagnosed as having Kugelberg-Welander disease, grand mal seizures and urinary dysfunction. Their parents and grandparents had consanguinity. Three relatives were found to have deaf-mutism without accompanying ophthalmoplegia. This rare combination of mitochondrial encephalomyopathy and familial deaf-mutism might be caused by a nuclear DNA mutation in these sisters.