It has recently been proposed, on the basis of a theoretical analysis, that the folding of the mucosa provides a significant component of airway stiffness. The model predicted that the stiffness of an airway was directly related to the number of epithelial folds that developed. In this study we examine the possibility that the folding pattern is determined by the physical requirements that the folding membrane must stay within the boundary of the smooth muscle wall, that the submucosal mass is constant, and that the strain energy of the folding membrane is the minimum possible within the geometric constraints. Model predictions are compared with morphometric data from the noncartilaginous airways of 17 sheep lungs. The data are in agreement with our predictions, which are based on the assumption that the folding membrane thickness is proportional to the submucosal thickness (in a fully dilated airway). The outcome of this analysis is that the increase in intrinsic stiffness of the folding membrane resulting from the increased thickness outweighs the decrease in stiffness conferred by the fewer folds required by the thicker submucosa. It is suggested that the increase in folding membrane thickness observed in asthma could be viewed as a protective mechanism that tends to reduce hyperresponsiveness.