In patients with mild chronic obstructive pulmonary disease (COPD), the effect of deep inspirations (DIs) to reverse methacholine-induced bronchoconstriction is largely attenuated. In this study, we tested the hypothesis that the effectiveness of DI is reduced with increasing disease severity and that this is associated with a reduction in the ability of DI to distend the airways. Fifteen subjects [Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I–II: n = 7; GOLD stage III–IV: n = 8] underwent methacholine bronchoprovocation in the absence of DI, followed by DI. The effectiveness of DI was assessed by their ability to improve inspiratory vital capacity and forced expiratory volume in 1 s (FEV₁). To evaluate airway distensibility, two sets of high-resolution computed tomography scans [at residual volume (RV) and at total lung capacity] were obtained before the challenge. In addition, mean parenchymal density was calculated on the high-resolution computed tomography scans. We found a strong correlation between the response to DI and baseline FEV₁ %predicted ( r² = 0.70, P < 0.0001) or baseline FEV₁/forced vital capacity ( r² = 0.57, P = 0.001). RV %predicted and functional residual capacity %predicted correlated inversely ( r² = 0.33, P = 0.02 and r² = 0.32, P = 0.03, respectively), and parenchymal density at RV correlated directly ( r² = 0.30, P = 0.03), with the response to DI. Finally, the effect of DI correlated to the change in large airway area from RV to total lung capacity ( r² = 0.44, P = 0.01). We conclude that loss of the effects of DI is strongly associated with COPD severity and speculate that the reduction in the effectiveness of DI is due to the failure to expand the lungs because of the hyperinflated state and/or the parenchymal damage that prevents distension of the airways with lung inflation.