The effect of breathing helium-oxygen (He-O2) mixtures was evaluated in 15 patients with severe chronic obstructive pulmonary disease (COPD). Gas exchange was assessed during quiet breathing at rest before and after 15 minutes of breathing 80 percent He-20 percent O2 mixtures in all patients. Functional residual capacity (FRC) determined during argon (Ar) washing studies fell significantly while breathing He-O2, but we did not find significant changes in minute ventilation, tidal volume, respiratory frequency, or inspiratory or expiratory timing. Eleven patients showed decreases in arterial PCO2 and CO2 excretion during resting breathing on He-O2. Expiratory flows were increased at a given lung volume during He-O2 breathing as expected. Apparently, mechanical work of breathing was decreased in patients with severe COPD while breathing He-O2, leading to a reduction in VCO2 and improvement in overall alveolar ventilation. These findings lend support to the therapeutic use of He-O2 under some conditions in patients with severe COPD.