Extra-vehicular activity (EVA) during spaceflight involves a significant decompression stress. Previous studies have shown an increase in the inhomogeneity of ventilation-perfusion ratio (V_A/Q) following some underwater dives, presumably through the embolic effects of venous gas micro-emboli (VGE) in the lung. Ground-based chamber studies simulating EVA have shown that VGE occur in a large percentage of the subjects undergoing decompression, despite the use of pre-breathe protocols to reduce dissolved N₂ in the tissues. We studied 8 crewmembers (7 male, 1 female) of the International Space Station (ISS) who performed 15 EVAs (initial cabin pressure 748 mmHg, final suit pressure either ~295 mmHg or ~220 mmHg depending on the suit used) and who followed the denitrogenation procedures approved for EVA from the ISS. The intra-breath V_A/Q slope (iV/Q) was calculated from the alveolar PO₂ and PCO₂ in a prolonged exhalation maneuver on the day following EVA and compared with measurements made in microgravity on days well-separated from the EVA. There were no significant changes in iV/Q as a result of EVA although there was a slight increase in metabolic rate and ventilation (~9%) on the day following EVA. Vital capacity and other measures of pulmonary function were largely unaltered by EVA. Because measurements could only be performed on the day following EVA due to logistical constraints, we were unable to determine an acute effect of EVA on V_A/Q inequality. The results suggest that current denitrogenation protocols do not result in any major lasting alteration to gas exchange in the lung.