Oxidative stress has been suggested as a potential mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). It has been difficult to address this hypothesis because of the limitations of conventional indices of lipid peroxidation in vivo. F₂-isoprostanes (iPs) are prostaglandin isomers formed by free radical dependent peroxidation of arachidonic acid. Urinary iPF_{2 α}-III is a relatively abundant iPs produced in humans. In the present study, we investigated whether COPD is associated with enhanced oxidative stress by measuring urinary levels of this compound. Urinary excretion of iPF_{2 α}-III was determined in 38 patients with COPD and 30 sex- and age-matched healthy control subjects. Levels of iPF_{2 α}-III were significantly higher in patients with COPD (median, 84 pmol / mmol creatinine; range, 38 to 321) than in healthy controls (median, 35.5 pmol / mmol creatinine; range, 15 to 65) (p < 0.0001). This elevation was independent of age, sex, smoking history, or duration of the disease. An inverse relationship was observed with the level of Pa_O2 (r = − 0.38, p = 0.019). Aspirin treatment failed to decrease urinary levels of iPF_{2 α}-III (102 ± 8 versus 99.2 ± 7.3 pmol / mmol creatinine), whereas 11-dehydro TxB₂ was significantly reduced (695 ± 74 versus 95 ± 10 pmol / mmol creatinine) (p < 0.0001). Elevated levels of iPF_{2 α}-III (median, 125 pmol / mmol creatinine; range, 110 to 170) in five patients with COPD declined (median, 90 pmol / mmol creatinine; range, 70 to 110) (p < 0.001) as an acute exacerbation in their clinical condition resolved. Increased urinary iPF_{2 α}-III is consistent with the hypothesis that oxidative stress occurs in COPD. This provides a basis for dose finding and evaluation of antioxidant therapy in the treatment of this disease.