Model studies incorporating known morphological properties of the airways predict different narrowing characteristics between large and small bronchi. However, the flow-response characteristics of airways from different regions in the bronchial tree are still unknown.We compared the responsiveness of large and small bore bronchi of the pig to luminal or adventitial stimulation by acetylcholine (ACh) during perfusion of the airways at optimal driving pressure. Subsequently, each segment was measured morphometrically. Resting flow through the lumen was directly related to the fourth power of the segment internal diameter (ID). The sensitivity of small bronchi (2.00 mm ID) to ACh applied adventitially was about 870 times greater than large (5.85 mm ID) with a longer latency time of contraction in large bronchi.When perfused luminally the sensitivity difference was 42 fold, and after removing the epithelium the sensitivity difference was reduced to approximately five fold. Maximum concentrations of ACh produced airway closure in small segments (100% reduction in flow) but in large segments a plateau developed at 60-90% flow reduction. Similar findings were obtained with carbachol. Morphometry of the airway wall showed increasing cartilage, mucosal and smooth muscle thickness with increasing diameter, but a decreasing relative wall area.The marked differences in sensitivity to narrowing between large and small bronchi are, in part, related to differences in morphological properties of the mucosa (the epithelium) and adventitia, and to airway location. Airway size plays an important role in the maximum response of airway narrowing, with small airways showing closure and large airways a plateau.