Exercise can distend the normally compliant, thin-walled pulmonary vessels. Loss of distensibility has been suggested as an early marker of pulmonary vascular remodeling. We hypothesized that in mild pulmonary vascular disease (PVD), a reduction in vascular distensibility during exercise occurs prior to the development of overt resting pulmonary hypertension (PH). Distensibility α during exercise (percentage change in vessel diameter per mm Hg increase in transmural pressure) was estimated in 90 subjects using a model of the pulmonary circulation and invasive hemodynamic data. Distensible properties in mild PVD without resting PH (PVD-noPH) (n = 33) were compared with control subjects (n = 26) and PVD with overt resting PH (PVD-PH) (n = 31). Resting mean pulmonary artery pressure (mPpa) levels were 14 ± 4, 20 ± 3, and 34 ± 10 mm Hg with corresponding exercise mPpa-cardiac output slopes of 1.5 ± 0.6, 3.5 ± 0.9, and 5.7 ± 3.2 mm Hg/L/min for control subjects and the PVD-noPH and PVD-PH groups, respectively. The distensible model produced high accuracy and precision with no mean bias and 95% limits of agreement of -4.5 to 4.5 mm Hg between calculated and measured mPpa. Distensibility α was lowest in the PVD-PH group, intermediate in the PVD-noPH group, and highest in control subjects (0.25 ± 0.14%/mm Hg vs 0.45 ± 0.24%/mm Hg vs 1.40 ± 0.45%/mm Hg, P < .0001). Distensibility α discriminated PVD-noPH from control subjects with a sensitivity of 88% and a specificity of 100%. The discriminatory performance of α was similar for the subgroup of PVD-noPH, with a strictly normal resting mPpa ≤ 20 mm Hg. Loss of pulmonary vascular distensibility during exercise occurs prior to resting PH in PVD. The usefulness of α as a novel vascular index for the early detection of PVD warrants further validation.