Background: High flow nasal cannula therapy (HFNC) has been widely adopted for respiratory distress, and evidence suggests that purging dead space of the upper airway improves gas fractions in the lung. This study tests the hypothesis that HFNC with room air could be as effective as low flow oxygen in chronic obstructive pulmonary disease (COPD). Methods: Thirty-two COPD patients prescribed 1 - 2 L/min of oxygen were studied. The conditions tested consisted of a control (CTRL; no therapy), then in random order HFNC and prescribed low flow oxygen (LFO). HFNC was the highest flow tolerated up to 35 L/min without supplemental oxygen. Arterial blood gases (ABGs), respiratory rate (RR), heart rate (HR) and tidal volume (VT) were measured at the end of each condition. Results: Arterial oxygen (PaO2) was greater (p < 0.001) for LFO than both HFNC and CTRL (CTRL=57.4±6.1mmHg, HFNC=58.6±8.3mmHg, LFO=72.6±10.2mmHg). HFNC reduced RR by 11% (p<0.05) from CTRL and LFO (CTRL=20.2±3.8br/min, HFNC=17.9±3.3br/min, LFO=20.2±3.7br/min) with no differences in VT. There were no differences between arterial carbon dioxide (PaCO2) (CTRL=45.5±4.9mmHg, HFNC=45.0±5.3mmHg, LFO=46.0±3.9mmHg). Conclusions: HFNC resulted in a clinically relevant reduction in ventilatory effort with no change in ABG indicating a gas equilibrium effect of purging anatomical dead space. Clinical Trial Registration: ClinicalTrials.gov ID: NCT00990210.