The objective of this study was evaluate the relationships between abnormal pulmonary circulation, lung function, and respiratory response during exercise in Fontan patients. Pulmonary function and cardiopulmonary exercise tests were performed in 101 Fontan patients and 122 controls. A small vital capacity (VC) with a high residual volume-to-total lung capacity ratio and a slight but significant low arterial saturation with hypocapnia were observed in Fontan patients. The number of surgical procedures determined VC. Total cavopulmonary connection, fenestration, higher pulmonary arterial wedge pressure, and smaller VC were independent determinants of low arterial saturation, which was the only determinant of hypocapnia. Arterial saturation decreased during exercise and resting arterial saturation correlated with that at peak exercise. Improvement in dead space ventilation was less in Fontan patients and was independently determined by resting arterial saturation. A steeper minute ventilation-carbon dioxide production slope was determined by resting arterial saturation, arterial carbon dioxide tension, and peak oxygen uptake. In Fontan patients, in addition to dead space ventilation, surgery-related reduced VC, the type of repair, and high pulmonary arterial wedge pressure cause arterial desaturation with subsequent hypocapnia, resulting in accelerated inefficient ventilation at rest and during exercise.