Mitochondrial cytopathies are multisystemic disorders of extremely variable expression due to a deficiency in oxidative phosphorylation. Cases have recently been reported in which fatal liver failure with neonatal onset was the major clinical and biochemical syndrome. In this series we reviewed the liver histology of 10 such patients who died in the first weeks of life (from 3 days to 6 mo). In six cases the diagnosis was confirmed by study of the mitochondrial respiratory chain in the muscle, liver or both; in the other four, appropriate tests were not available for diagnosis but symptoms were identical and all other diagnoses were ruled out. In all 10 cases we noted significant steatosis, mostly microvesicular; widespread hepatocytic, canalicular and bile duct cholestasis with bile thrombi and cholangiolar proliferation; and different degrees of hepatosiderosis and glycogen depletion. Fibrosis took varying forms: perisinusoidal, periportal with the formation of septa, even precirrhosis. In the two cases of infants who died, one at 5 and one 6 mo, micronodular cirrhosis was also present. Mitochondria, either densely or loosely packed, were abnormal–pleiomorphic with few or no cristae and a granular fluffy matrix. Dense, large granules were seen in two cases. The association of neonatal liver failure and hyperlactacidemia should lead to immediate examination of the respiratory chain. The expression of this mitochondrial cytopathy can be lethal, associated with severe liver damage due to the deficiency in oxidative phosphorylation. (HEPATOLOGY 1993;18:839-846).