Background Impaired skeletal muscle function contributes to exercise intolerance in patients with COPD. Exercise-induced oxidative stress may initiate or accelerate impaired muscle function. Dichloroacetate (DCA) activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and thereby diminishing anaerobic energy production. This study aimed to determine whether DCA infusion may also reduce exercise-induced systemic oxidative stress and inflammatory response in COPD patients. Methods A randomized, double-blind crossover design was used in which thirteen COPD patients performed maximal cycle exercise after an IV infusion of DCA (50mg/kilogram body mass) or saline (placebo). Venous blood was sampled before, immediately after, 30 min and 2h after exercise. Urine samples were obtained before and 2h after exercise. Results Peak workload improved significantly after DCA compared to placebo (10%; p < 0.01). Urinary uric acid after exercise was significantly lower in the DCA condition when compared to placebo, whereas no significant difference was observed for urinary malondialdehyde. Oxidized glutathione (GSSG) was significantly increased 2h after exercise in the placebo condition (p < 0.02), but not after DCA. No changes in reduced glutathione (GSH), GSSG/GSH ratio and superoxide dismutase activity were observed. Plasma IL-6 significantly increased 2h after exercise only in the DCA condition (p < 0.01). Conclusions This study shows that the improved performance after a pharmacological intervention known to activate PDC was accompanied by an enhanced IL-6 response and a limited reduction in exercise-induced systemic oxidative stress. Trial registration National Research Register (www.nrr.nhs.uk) Identifier: N0123180712.