Background Airway wall thickening is commonly quantified at chest CT with Pi10, the square root of the wall area of a hypothetical airway with a luminal perimeter of 10 mm. Although Pi10 has proven to be a useful construct, it assumes uniform thickening of all airways and considers only a single airway level in summarizing airway remodeling, limiting its accuracy. Purpose To evaluate PiSlope, a new metric for the quantification of airway wall thickening. Materials and Methods In this secondary analysis of data from a multicenter prospective study of individuals who currently smoke or formerly smoked as well as healthy volunteers who never smoked enrolled from January 2008 to June 2011 and followed up longitudinally until September 2022, chest CT images were analyzed section by section to quantify the luminal perimeter and airway wall thickness for each visible airway. Linear regression was used to calculate the slope of the luminal perimeter against wall thickness to determine the PiSlope. PiSlope was normalized by the individual's height squared. Multivariable regression was used to test the associations between airway metrics and respiratory outcomes. Results The mean age of the 8199 participants was 59.5 years ± 9.1 (SD), with 53% male and 67% White participants. With increasing disease severity (ie, Global Initiative for Chronic Obstructive Lung Disease stages 0-4), Pi10 increased (4.26 mm ± 0.23, 4.29 mm ± 0.21, 4.43 mm ± 0.26, 4.51 mm ± 0.28, and 4.53 mm ± 0.27, respectively) and PiSlope decreased (0.38 ± 0.10, 0.38 ± 0.10, 0.35 ± 0.11, 0.33 ± 0.10, and 0.31 ± 0.10) (trend test; both P < .001). Multivariable analyses revealed that PiSlope was associated with dyspnea, respiratory quality of life, 6-minute walk distance, exacerbations, lung function decline, and all-cause mortality, with and without Pi10 being included in the model. Conclusion The new metric PiSlope quantifies airway wall remodeling and shows associations with respiratory symptoms, quality of life, exacerbations, lung function decline, and all-cause mortality. Clinical trial registration no. NCT00608764 © RSNA, 2024 See also the editorial by Lynch in this issue.