OBJECTIVES: Transbronchial lung cryobiopsy (TBLC) has been identified to be a new technique to diagnosis interstitial lung disease (ILD). The study was conducted to investigate the safety and the diagnostic accuracy of TBLC contrast with transbronchial lung biosy (TBLB) in patients with ILD. METHODS: In a cross-sectional and comparative study, patients with suspected ILD who underwent TBLC or TBLB were evaluated from June 2018 to September 2022 in Nanjing drum tower hospital. TBLC and TBLB procedure details and clinical multidisciplinary discussion (MDD) diagnosis based on clinical, radiological, and histopathological information were retrospectively analyzed. Diagnostic yield and complications of TBLC and TBLB were evaluated. RESULTS: 187 patients who underwent TBLC and 176 patients who underwent TBLB following a standardized protocol were enrolled. The diagnostic yield of TBLC and TBLB in patients with ILD were 85.0% and 63.1%, respectively. In TBLC, 162 patients (86.6%) had no or mild bleeding and 25 patients (13.4%) had moderate bleeding. None of the patients had severe bleeding and the rate of pneumothorax was 14.4%. Comparatively, pooled incidences of complications were 91.5% for no or mild bleeding, 8.5% for moderate bleeding and 5.1% for pneumothorax after TBLB. There was no difference in the occurrence of bleeding among TBLC group and TBLB group. CONCLUSIONS: This study indicated that the clinical applicability of TBLC in ILD diagnostic algorithms, with a diagnostic yield of 85.0% and an acceptable safety profile.