Nitroglycerin, 0.6 mg sublingually, was given to 27 nonasthmatic subjects with varying degrees of airways dysfunction to determine the effect on arterial oxygenation. In six normal subjects, the partial pressure of oxygen in arterial blood (Pao2) transiently decreased by 9 mm Hg (p less than 0.05) and in eight subjects with only small airways dysfunction, the Pa02 decreased by 14 mm Hg (p less than 0.0001). The alveolar-arterial oxygen gradient on oxygen increased by only 11 mm Hg indicating that the decrease in room air Pao2 was primarily due to worsening ventilation-perfusion mismatch and not to an increase in shunt. Thirteen subjects with advanced obstructive or restrictive lung disease experienced a much lesser decrease in Pao2 of 4 mm Hg. Data are presented on xenon perfusion studies of a dog model of unilateral alveolar hypoxia that suggest the worsening ventilation-perfusion ratio seen in the human subjects after the administration of nitroglycerin could be due to loss of the lung's ability to vasoconstrict in regions of alveolar hypoxia and shift perfusion to better ventilated regions of the lung.