ObjectivesTo assess the value of quantitative computed tomography (QCT) of the whole lung and nodule-bearing lobe regarding pulmonary nodule malignancy risk estimation.MethodsA total of 251 subjects (median [IQR] age,65 (57–73) years; 37% females) with pulmonary nodules on non-enhanced thin-section CT were retrospectively included. Twenty percent of the nodules were malignant, the remainder benign either histologically or at least 1-year follow-up. CT scans were subjected to in-house software, computing parameters such as mean lung density (MLD) or peripheral emphysema index (pEI). QCT variable selection was performed using logistic regression; selected variables were integrated into the Mayo Clinic and the parsimonious Brock Model.ResultsWhole-lung analysis revealed differences between benign vs. malignant nodule groups in several parameters, e.g. the MLD (−766 vs. −790 HU) or the pEI (40.1 vs. 44.7 %). The proposed QCT model had an area-under-the-curve (AUC) of 0.69 (95%-CI, 0.62−0.76) based on all available data. After integrating MLD and pEI into the Mayo Clinic and Brock Model, the AUC of both clinical models improved (AUC, 0.91 to 0.93 and 0.88 to 0.91, respectively). The lobe-specific analysis revealed that the nodule-bearing lobes had less emphysema than the rest of the lung regarding benign (EI, 0.5 vs. 0.7 %;p< 0.001) and malignant nodules (EI, 1.2 vs. 1.7 %;p= 0.001).ConclusionsNodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant; hereby the nodule-bearing lobes have less emphysema. QCT variables could improve the risk assessment of incidental pulmonary nodules.Key Points• Nodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant.• The nodule-bearing lobes have less emphysema compared to the rest of the lung.• QCT variables could improve the risk assessment of incidental pulmonary nodules.