In order to determine the effect of breathing high fractional concentrations of oxygen on forced expiratory flow in individuals with chronic obstructive pulmonary disease (COPD), we studied 18 patients with moderately severe disease. The patients were studied breathing air, 100% oxygen, or a four-gas mixture in a randomized double-blind study design. The four-gas mixture (oxygen 21.0%, argon 48.6%, nitrogen 19.3%, and helium 11.1%) was calculated to have a density and viscosity similar to oxygen. During spirometric testing, breathing oxygen produced a detectable reduction in timed volumes by 1 minute that was sustained at 5 minutes (FEVi reduction 4.9% at 1 minute and 6.3% at 5 minutes). Breathing the gas mixture for 5 minutes resulted in similar reductions in flow. We conclude that high concentrations of oxygen reduce forced expiratory flow in patients with airflow obstruction, an effect probably related to the increased density and viscosity relative to air. This reduction in forced expiratory flow may contribute to the deterioration seen when COPD patients with acute respiratory failure are treated with 100% oxygen.