Oxidative stress may contribute to exercise intolerance in patients with COPD. This study sought to determine the effect of an acute oral antioxidant cocktail (AOC: vitamins C, E, and alpha‐lipoic acid) on skeletal muscle function in patients with COPD. Ten patients with COPD (FEV1/FVC < 0.7, FEV1 ≤ 80% predicted) performed knee extensor exercise to exhaustion as well as isotime trials following either the AOC or placebo. Changes in quadriceps maximal voluntary contractions (MVCs) and potentiated twitch forces (Qtw,pot) quantified quadriceps fatigue. Despite increasing plasma ascorbate levels (10.1±2.2 to 24.1±3.8 ug/ml, p<0.05) and attenuating the electron paramagnetic resonance (EPR) spectroscopy free radical signal (AUC: 11.6±3.7 to 4.8±2.2 AU, p<0.05), AOC consumption did not alter endurance time or the development of quadriceps fatigue. Revaluation of the EPR spectroscopy data revealed that the AOC was most efficacious in patients with high (n=5, AUC: 19.7±5.8 to 5.8±4.5 AU) compared to low (n=4, AUC: 1.6±0.5 to 3.4±1.1 AU) basal free radical levels. This baseline index of free radicals was inversely correlated with FEV1 (r=−0.54, p<0.05) and MVC force (r=−0.56, p<0.05). Thus, while a potentially beneficial role for the AOC in COPD can be inferred, an acute reduction in free radicals does not appear to influence exercise performance in COPD. Supported by the National Institutes of Health grant PO1 HL 09830.