Mechanisms of gas-exchange impairment in idiopathic pulmonary fibrosis. To investigate the mechanisms of pulmonary gas-exchange impairment in idiopathic pulmonary fibrosis (IPF) and to evaluate their potential relationship to the CO diffusing capacity (DLCO), we studied 15 patients with IPF (mean DLCO, 52% of predicted) at rest (breathing room air and pure O2) and during exercise. We measured pulmonary hemodynamics and respiratory gas-exchange variables, and we separated the ventilation-perfusion (VAQ) mismatching and O2 diffusion limitation components of arterial hypoxemia using the multiple inert gas elimination technique. At rest VA/Q mismatching was moderate (2 to 4% of cardiac output perfusing poorly or unventilated lung units), and 19% of AaPO2 was due to O2 diffusion limitation. During exercise VA/Q mismatch did not worsen but the diffusion component of arterial hypoxemia increased markedly (40% AaPO2, p less than 0.005). We observed that those patients with higher pulmonary vascular tone (more release of hypoxic pulmonary vasoconstriction) showed less pulmonary hypertension during exercise (p less than 0.05), less VA/Q mismatching [at rest (p less than 0.005) and during exercise (p less than 0.0025)], and higher arterial PO2 during exercise (p = 0.01). We also found that DLCO corrected for alveolar volume (KCO) correlated with the mechanisms of hypoxemia during exercise [VA/Q mismatching (p less than 0.025) and O2 diffusion limitation (p less than 0.05)] and with the increase in pulmonary vascular resistance elicited by exercise (p less than 0.005). In conclusion, we showed that the abnormalities of the pulmonary vasculature are key to modulate gas exchange in IPF, especially during exercise. 