Cytochrome-c-oxidase, the terminal enzyme of the respiratory chain, was studied in 140 hearts from men obtained at autopsy revealing randomly distributed cardiomyocytes without enzyme activity. The expression of the defect was independent of an underlying heart disease and was observed both in normal hearts and in hearts with hypertrophy and/or coronary arteriosclerosis. In contrast, age was a discriminating factor: The defects occurred sporadically in the second decade, but were regularly present from the sixth decade on. Also, the number of defects/sq cm (defect density) increased with age from 2 to 3 in the second and third decade, to about 50 defects in advanced age. Irrespective of the defect density, the enzyme defect always affected isolated cardiomyocytes and ended abruptly at the intercalated disc of neighboring heart muscle cells, as revealed by ultracytochemistry. The results indicate that cytochrome-c-oxidase deficient heart muscle cells represent a degenerative lesion associated with cellular ageing and may be involved in the reduction of myocardial contractile ability in senescence.