We have studied the influence of pulmonary vascular tone on ventilation-perfusion relationships in subjects with chronic obliterative pulmonary vascular disease. We administered oxygen, isoproterenol, or nitroprusside on 15 occasions in 7 subjects and observed a fall in pulmonary vascular resistance of greater than 15% in 8 of these 15 trials. When pulmonary vascular resistance was reduced, there was an increase in the perfusion of lung units with low ventilation-perfusion ratios (VA/Q) and/or shunt as determined by the multiple inert gas technique. The pattern of increased VA/Q inequality was independent of the specific agent used. In only one instance in which pulmonary vascular resistance was not reduced did drug administration lead to a worsening of VA/Q relationships. The detrimental effect of the increased perfusion of low VA/Q units on arterial oxygenation was frequently attenuated by an increased mixed venous oxygen content due to an increase in total cardiac output. We conclude that pulmonary vascular tone contributes to the maintenance of VA/Q matching in subjects with obstruction of the pulmonary vascular bed.