The abnormalities of gas exchange at rest and during mild exercise were characterized in 6 adults with cystic fibrosis. All patients were hypoxemic at rest with a venous admixture ranging from 9.8 to 39.9%. Using the technique of multiple inert gas elimination we demonstrated that all 6 patients had significant intrapulmonary shunt and that this accounted for most of the venous admixture in three patients. In the remaining three patients there was, in addition, significant perfusion to lung units with low ventilation-perfusion ratios (VA/Q). The abnormalities of VA/Q adequately accounted for the measured arterial blood gases and no diffusion impairment for oxygen was noted. During exercise there was an improvement in the efficiency of gas exchange, but there were only minimal changes in the arterial PO2. This resulted from a widened arteriovenous O2 difference and in 2 patients an increase in shunt. The consistent presence of shunt and variability of the pattern of the VA/Q distributions differ from previously described studies in other patients with chronic airway obstruction.