Evidence suggests damage to small airways is a key pathologic lesion in chronic obstructive pulmonary disease (COPD). Computed tomography densitometry has been demonstrated to identify emphysema, but no such studies have been performed linking an imaging metric to small airway abnormality. To correlate parametric response mapping (PRM) analysis to lung tissue measurements of patients with severe COPD treated by lung transplantation and control subjects. Resected lungs were inflated, frozen, and systematically sampled, generating 33 COPD ( = 11 subjects) and 22 control tissue samples ( = 3 subjects) for micro-computed tomography analysis of terminal bronchioles (TBs; last generation of conducting airways) and emphysema. PRM analysis was conducted to differentiate functional small airways disease (PRM) from emphysema (PRM). In COPD lungs, TB numbers were reduced ( = 0.01); surviving TBs had increased wall area percentage ( < 0.001), decreased circularity ( < 0.001), reduced cross-sectional luminal area ( < 0.001), and greater airway obstruction ( = 0.008). COPD lungs had increased airspace size ( < 0.001) and decreased alveolar surface area ( < 0.001). Regression analyses demonstrated unique correlations between PRM and TBs, with decreased circularity ( < 0.001), decreased luminal area ( < 0.001), and complete obstruction ( = 0.008). PRM correlated with increased airspace size ( < 0.001), decreased alveolar surface area ( = 0.003), and fewer alveolar attachments per TB ( = 0.01). PRM identifies areas of lung tissue with TB loss, luminal narrowing, and obstruction. This is the first confirmation that an imaging biomarker can identify terminal bronchial pathology in established COPD and provides a noninvasive imaging methodology to identify small airway damage in COPD.