Extravehicular activity (EVA) during spaceflight involves a significant decompression stress. Previous studies have shown an increase in the inhomogeneity of ventilation-perfusion ratio (V̇a/Q̇) after some underwater dives, presumably through the embolic effects of venous gas microemboli in the lung. Ground-based chamber studies simulating EVA have shown that venous gas microemboli occur in a large percentage of the subjects undergoing decompression, despite the use of prebreathe protocols to reduce dissolved N2 in the tissues. We studied eight crewmembers (7 male, 1 female) of the International Space Station who performed 15 EVAs (initial cabin pressure 748 mmHg, final suit pressure either ∼295 or ∼220 mmHg depending on the suit used) and who followed the denitrogenation procedures approved for EVA from the International Space Station. The intrabreath V̇a/Q̇ slope was calculated from the alveolar Po2 and Pco2 in a prolonged exhalation maneuver on the day after EVA and compared with measurements made in microgravity on days well separated from the EVA. There were no significant changes in intrabreath V̇a/Q̇ slope as a result of EVA, although there was a slight increase in metabolic rate and ventilation (∼9%) on the day after EVA. Vital capacity and other measures of pulmonary function were largely unaltered by EVA. Because measurements could only be performed on the day after EVA because of logistical constraints, we were unable to determine an acute effect of EVA on V̇a/Q̇ inequality. The results suggest that current denitrogenation protocols do not result in any major lasting alteration to gas exchange in the lung.