We assessed whether melatonin administration would prevent the hyperoxidative status that occurs in lung mitochondria with age. Mitochondria from lungs of male and female senescent prone mice at 5 and 10 months of age were studied. Age-dependent mitochondrial oxidative stress was evaluated by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and reductase activities. Mitochondrial respiratory chain and oxidative phosphorylation capability were also measured. Age induces a significant oxidative/nitrosative status in lung mitochondria, which exhibited a significantly reduced activity of the respiratory chain and ATP production. These manifestations of age were more pronounced in males than in females. After 9 months of melatonin administration in the drinking water, the hyperoxidative status and functional deficiency of aged lung mitochondria were totally counteracted, and had increased ATP production. The beneficial effects of melatonin were generally similar in both mice genders. Thus, melatonin administration, as a single therapy, maintained fully functioning lung mitochondria during aging, a finding with important consequences in the pathophysiology of lung aging. In view of these data melatonin, the production of which decreases with age, should be considered a preventive therapy against the hyperoxidative status of the aged lungs, and its use may lead to the avoidance of respiratory complications in the elderly.