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 (Dl_CO)> we studied 15 patients with IPF (mean Dl_CO, 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 (a) mismatching and O₂ diffusion limitation components of arterial hypoxemia using the multiple inert gas elimination technique. At rest a/ mismatching was moderate (2 to 4% of cardiac output perfusing poorly or unventilated lung units), and 19% of AaP_O2 was due to O₂ diffusion limitation. During exercise a/ mismatch did not worsen but the diffusion component of arterial hypoxemia increased markedly (40% AaP_O2, p < 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 < 0.05), less a/ mismatching [at rest (p < 0.005) and during exercise (p < 0.0025)], and higher arterial P_O2 during exercise (p = 0.01). We also found that Dl_CO corrected for alveolar volume (Kco) correlated with the mechanisms of hypoxemia during exercise [a/ mismatching (p < 0.025) and O₂ diffusion limitation (p < 0.05)] and with the increase in pulmonary vascular resistance elicited by exercise (p < 0.005). In conclusion, we showed that the abnormalities of the pulmonary vasculature are key to modulate gas exchange in IPF, especially during exercise. We recommend the routine correction of Dl_CO for alveolar volume (Kco) in the clinical assessment of patients with IPF because the latter seems to be a useful functional indicator of both the severity of gas-exchange impairment during exercise and the degree of pulmonary vascular involvement.