BackgroundPrior studies have noted that patients with interstitial lung disease (ILD) possess an increased incidence of lung cancer and risk of postoperative respiratory failure and death. We sought to understand the impact of ILD on national-scale outcomes of lung resection. MethodsA retrospective cohort analysis using The Society of Thoracic Surgeons General Thoracic Surgery Database was conducted of patients who underwent a pulmonary resection for non-small cell lung cancer between 2009 and 2019. Baseline characteristics and postoperative outcomes were compared between patients with and without ILD (defined as interstitial fibrosis based on clinical, radiographic, or pathologic evidence). Multivariable logistic regression models identified risk factors associated with postoperative mortality, acute respiratory distress syndrome, and composite morbidity and mortality. ResultsILD was documented in 1.5% (1873 of 128,723) of patients who underwent a pulmonary resection for non-small cell lung cancer. Patients with ILD were more likely to smoke (90% vs 85%, P < .001), have pulmonary hypertension (6% vs 1.7%, P < .001), impaired diffusing capacity of lung for carbon monoxide (diffusing capacity of lung for carbon monoxide 40%-75%: 64% vs 51%; diffusing capacity of lung for carbon monoxide <40%: 11% vs 4%, P < .001), and undergo more sublobar resections (34% vs 23%, P < .001) compared with patients without ILD. Patients with ILD had increased postoperative mortality (5.1% vs 1.2%, P < .001), acute respiratory distress syndrome (1.9% vs 0.5%, P < .001), and composite morbidity and mortality (13.2% vs 7.4%, P < .001). ILD remained a strong predictor of mortality (odds ratio, 3.94; 95% CI, 3.09-5.01; P < .001), even when adjusted for patient comorbidities, pulmonary function, extent of resection, and center volume effects. ConclusionsILD is a risk factor for operative mortality and morbidity after lung cancer resection, even in patients with normal pulmonary function.