Clinical symptoms of acute carbon monoxide (CO) poisoning are mainly related to the capability of haemoglobin to bind CO. However, the persistence of some clinical alterations after carboxyhaemoglobin normalization suggests that other heme containing proteins, like cytochrome c oxidase, could play a role in its pathogenesis. We studied mitochondrial enzyme activities of lymphocytes from three patients suffering from acute CO poisoning. HbCO levels were 11.6%. 19.6% and 22.3% in the acute phase, 2.3%, 2.4% and 1.5% on day 3 after admission, and 1.2%, 3.3% and 1.1% on day 12. Complex II, III and glycerol-3-phosphate dehydrogenase activities remained normal along the study, while cytochrome c oxidase (complex IV) activity showed a 76% inhibition compared to controls during acute poisoning (P < 0.01) and 48% at day 3 (P < 0.05). The activity was normal already on day 12 after the complete disappearance of symptomatology. Our results suggest that mitochondrial cytochrome c oxidase is also a target site in human acute CO poisoning, and its extended and generalized inhibition could explain the persistence of different symptoms after the normalization of HbCO levels.