Background: To evaluate the effect of interstitial lung disease (ILD) on postoperative morbidity and mortality in pulmonary resection and identify the factors of AE-ILD. Methods: We retrospectively analyzed 1,309 patients underwent pulmonary operation between January 2010 and January 2018 in our hospital. Clinical data including age, sex, history of chronic obstructive pulmonary disease (COPD), smoking history, smoking index, American Society of Anesthesiologists (ASA) classification, Charlson comorbidity index (CCI), forced expiratory volume in 1 s (FEV1) % predict, surgical procedure, video-assisted thoracoscopic surgery (VATS) or not, intraoperative blood transfusion, anesthesia time, operation time/one-lung ventilation time, blood loss, histology, postoperative morbidity, 90-day mortality, onset of acute exacerbation of ILD (AE-ILD), and postoperative stay were collected and analyzed. Results: There were 97 (7.4%) and 1,212 (92.6%) patients in the ILD and non-ILD groups, respectively. AE-ILD occurred in 6 patients (0.5%), with a mortality of 83.3%, and was the leading cause of 90-day mortality (55.6%). Age (P<0.001) was an independent risk factor for ILD. There were 6 and 91 patients in the AE-ILD and non-AE-ILD groups, respectively. ASA classification (P=0.038) were independent risk factors for AE-ILD. Multivariate regression analysis identified that the sex (P=0.003), ILD (P<0.001), COPD (P=0.007), surgical procedure (P<0.001), blood loss (P<0.001), CCI (P=0.049) were independent risk factors for postoperative morbidity. ILD (P=0.001) and postoperative morbidity (P=0.003) were independent risk factors for 90-day mortality in multivariate analysis. Conclusions: Patients with ILD had a higher incidence of postoperative morbidity and 90-day mortality. ASA classification was an important influencing factor for AE-ILD. Based on the obvious postoperative morbidity and mortality, special attention and management should be given to ILD patients.