A black male and a white female neonate presented with respiratory distress, profound metabolic acidosis and progressive cardiac failure. Cytochrome oxidase deficiency was demonstrated in skeletal muscles in both cases. Both babies were treated with L-carnitine without response and died after 18 days. On postmortem examination, hypertrophic Cardiomyopathy was found to be the main cause of their demise. Histologic brain studies showed focal gliosis and lesions suggestive of Leigh's disease were absent. Light and electron microscopic examinations, histochemical and biochemical studies were performed on cardiac muscle and skeletal muscles in both cases, and mitochondrial enzyme profile on fibroblast culture in one case. Fatal cardiomyopathy occurring in infancy is known to be associated with several metabolic disorders, notably Pompe's disease and system carnitine deficiency. Cardiomyopathy associated with cytochrome oxidase deficiency, a recently described mitochondrial disorder associated with early death in infancy, has not been described. Cytochrome oxidase deficiency needs to be included in the increasing list of causes of Cardiomyopathy, especially those occurring in early childhood.