Exercise intolerance is an important predictor of mortality in patients with COPD, and evidence shows reduced nitric oxide (NO) bioavailability is a contributing factor. Thus, restoration of NO using BH4, a cofactor involved in NO production, is a novel therapy for improving oxygenation and metabolism in these patients. Patients with COPD performed dynamic plantar flexion exercise with 31P-MRS and vascular Doppler ultrasound assessments following supplementation of BH4. Limb blood flow during exercise was unchanged, however, exercise-induced changes in metabolic measurements were improved with BH4 supplementation. Therefore, BH4 supplementation in patients with COPD appears a promising therapy to improve muscle metabolism.