Cerebral oxygen and glucose metabolism have been studied in 8 patients with biochemically defined mitochondrial myopathies and 7 normal control subjects using positron emission tomography. Four patients had myopathy alone and 4 had predominantly central nervous system (CNS) disease. Cerebral oxygen and glucose metabolism were measured concurrently in the two groups of patients with 15O, 11C and 18F labelled tracers and positron emission tomography (PET). Patients with major CNS disease showed an uncoupling of glucose and oxygen metabolism when compared with patients without cerebral disease and normal subjects. The mean ratio between oxygen and glucose utilization was 3.8 moles of oxygen per mole of glucose in patients with CNS disease, compared with 5.6 for controls and 6.4 for patients with myopathy alone. The altered stoichiometry in CNS cases indicates aerobic glycolysis to lactate and/or other intermediate metabolites. Patients with major CNS disease showed a 50% reduction in cerebral oxygen utilization compared with cerebrally unaffected patients and normal subjects. These findings indicate that in patients with a mitochondrial encephalopathy the defect identified in skeletal muscle is also expressed in the brain.