Airway remodeling, a key feature of asthma, alters every layer of the airway wall but most strikingly the airway smooth muscle (ASM) layer. Airway remodeling in asthmatics contributes to fixed airflow obstruction and can amplify airway narrowing caused by ASM activation. Previous modeling studies have shown that the increase in ASM mass has the largest effect on increasing maximal airway narrowing. Simulated heterogeneity in the dimensions and properties of the airway wall can further amplify airway narrowing. Using measurements made on histological sections from donor lungs we show for the first time that there is profound heterogeneity of airway dimensions in both non-asthmatics and asthmatics. Using a mathematical model, we found that this heterogeneity contributes to an increased baseline resistance and elastance in asthmatics as well as a leftward shift in the responsiveness of the airways to a simulated agonist in both non-asthmatics and asthmatics. The ability of heterogeneous wall dimensions to shift the dose response curve is due to an increased susceptibility for the small airways to close. This research confirms that heterogeneity of airway wall dimensions can contribute to exaggerated airway narrowing and provides an actual assessment of the magnitude of these effects.