After pneumonectomy (Pnx), mechanical strain on the remaining lung is an important signal for adaptation. To examine how mechanical lung strain alters gas exchange adaptation after Pnx, we replaced the right lung of adult dogs with a custom-shaped inflatable silicone prosthesis. The prosthesis was kept 1) inflated (Inf) to reduce mechanical strain of the remaining lung and maintain the mediastinum in the midline, or 2) deflated (Def) to allow lung strain and mediastinal shift. Gas exchange was studied 4-7 mo later at rest and during treadmill exercise by the multiple inert gas elimination technique while animals breathed 21 and 14% O2 in balanced order. In the Inf group compared with Def group during hypoxic exercise, arterial O2 saturation was lower and alveolar-arterial O2 tension difference higher, whereas O2 diffusing capacity was lower at any given cardiac output. Dispersion of the perfusion distribution was similar between groups at rest and during exercise. Dispersion of the ventilation distribution was lower in the Inf group at rest, associated with a much higher respiratory rate, but rose to similar levels in both groups during hypoxic exercise. Mean pulmonary arterial pressure at a given cardiac output was higher in the Inf group, whereas peak cardiac output was similar between groups. Thus creating lung strain by post-Pnx mediastinal shift primarily enhances diffusive gas exchange with only minor effects on ventilation-perfusion matching, consistent with the generation of additional alveolar-capillary surfaces but not conducting airways and blood vessels.