Background: Age-related increases in morbidity and mortality due to asthma may be due to changes in pathophysiology as patients with asthma get older. There is limited knowledge about the effects of age on the predictors of airway hyperresponsiveness (AHR), a key feature of asthma. The aim of this study was to determine if the pathophysiologic predictors of AHR, including inflammation, ventilation heterogeneity, and airway closure, differed between young and old patients with asthma. Methods: Sixty-one young (18-46 years) and 43 old (50-80 years) patients with asthma had lung function, lung volumes, fraction of exhaled nitric oxide, ventilation heterogeneity, and airway responsiveness to methacholine measured. Airway response to methacholine was measured by the dose-response slope, as the percent fall in FEV 1 per micromole of methacholine. Indices of ventilation heterogeneity were calculated for convection-dependent and diffusion-dependent airways. Results: In young patients with asthma, the independent predictors of AHR were convection-dependent ventilation heterogeneity, exhaled nitric oxide, and % predicted FEV 1 /FVC (model r 2 =0.51, P < .0001). In old patients with asthma, the independent predictors of airway responsiveness were % predicted residual volume, diffusion-dependent ventilation heterogeneity, and % predicted FEV 1 (model r 2 = 0.57, P < .0001). Conclusions: In old patients with asthma, AHR is predicted by gas trapping and ventilation heterogeneity in peripheral, diffusion-dependent airways. In the young, it is predicted by ventilation heterogeneity in less peripheral conducting airways and by inflammation. These findings suggest that there are differences in the pathophysiologic determinants of AHR between young and old patients with asthma. © 2011 American College of Chest Physicians.