In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with (n = 8) or without (n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (approximately 75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4. 6 +/- 0.9% at rest vs. 9.3 +/- 1.7% after exercise). In nontreated patients, MDA increased from 0.68 +/- 0.08 nmol/ml at rest up to 1. 32 +/- 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 +/- 1.2% preexercise vs. 4.6 +/- 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 +/- 0.15 nmol/ml preexercise vs. 0.64 +/- 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.