This study aimed to evaluate how emphysema extent and its regional distribution quantified by chest CT are associated with clinical and functional severity in patients with chronic obstructive pulmonary disease (COPD). Patients with a post-bronchodilator forced expiratory volume in one second (FEV)/forced vital capacity (FVC) < 0.70, without any other obstructive airway disease, who presented radiological evidence of emphysema on visual CT inspection were retrospectively enrolled. A ntitative ung maging (QUALI) system automatically quantified the volume of pulmonary emphysema and adjusted this volume to the measured (EmphCT) or predicted total lung volume (TLV) (EmphP) and assessed its regional distribution based on an artificial neural network (ANN) trained for this purpose. Additionally, the percentage of lung volume occupied by low-attenuation areas (LAA) was computed by dividing the total volume of regions with attenuation lower or equal to -950 Hounsfield units (HU) by the predicted [LAA (%P)] or measured CT lung volume [LAA (%CT)]. The LAA was then compared with the QUALI emphysema estimations. The association between emphysema extension and its regional distribution with pulmonary function impairment was then assessed. In this study, 86 patients fulfilled the inclusion criteria. Both EmphCT and EmphP were significantly lower than the LAA indices independently of emphysema severity. CT-derived TLV significantly increased with emphysema severity (from 6,143 ± 1,295 up to 7,659 ± 1,264 ml from mild to very severe emphysema, < 0.005) and thus, both EmphCT and LAA significantly underestimated emphysema extent when compared with those values adjusted to the predicted lung volume. All CT-derived emphysema indices presented moderate to strong correlations with residual volume (RV) (with correlations ranging from 0.61 to 0.66), total lung capacity (TLC) (from 0.51 to 0.59), and FEV (0.6) and diffusing capacity for carbon monoxide DL (0.6). The values of FEV and DL were significantly lower, and RV ( < 0.001) and TLC ( < 0.001) were significantly higher with the increasing emphysema extent and when emphysematous areas homogeneously affected the lungs. Emphysema volume must be referred to the predicted and not to the measured lung volume when assessing the CT-derived emphysema extension. Pulmonary function impairment was greater in patients with higher emphysema volumes and with a more homogeneous emphysema distribution. Further studies are still necessary to assess the significance of CTpLV in the clinical and research fields.