Abstract: Chronic obstructive pulmonary disease (COPD), a major cause of death and disability, is attributed to an abnormal inflammatory response by the lungs to noxious substances, primarily from cigarette smoke. Although oxidative stress is regarded as central to the pathogenesis of COPD, very few studies have examined the effects of antioxidants in this condition. This was a randomized, double-blind, placebo-controlled study on the effects of melatonin in COPD. Thirty-six consecutive patients with clinically stable moderate to very severe COPD (30 men; mean ± S.D. = 66.6 ± 7.8 yr) were randomized to receive 3 mg melatonin (N = 18) or placebo for 3 months. Oxidative stress was evaluated by 8-isoprostane levels in exhaled breath condensate at baseline (T0) and after one (T1), two (T2), and three months (T3) of treatment. Additionally, exhaled breath condensate levels of IL-8, dyspnea severity (Medical Research Council scale), lung function (spirometry), and functional exercise capacity (six min walk test) were compared at baseline and after treatment. Patients receiving melatonin showed a decrease in 8-isoprostane (T0: mean ± S.E.M. = 20.41 ± 2.92 pg/mL; T1: 18.56 ± 2.68 pg/mL; T2: 12.68 ± 2.04 pg/mL; T3: 12.70 ± 2.18 pg/mL; P = 0.04; repeated measures ANOVA) with significant differences from baseline after 2 (P = 0.03) and 3 months (P = 0.01). Dyspnea was improved by melatonin (P = 0.01), despite no significant changes in lung function or exercise capacity. Placebo-treated patients, but not those who were given melatonin, showed an increase in IL-8 (P = 0.03). In summary, melatonin administration reduced oxidative stress and improved dyspnea in COPD. Further studies are necessary to determine the potential role for melatonin in the long-term management of these patients.