BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a novel technology in which a cryoprobe is used to obtain large tissue samples from the lungs of patients with interstitial lung diseases (ILDs) and peripheral pulmonary lesions (PPLs). We aimed to determine the efficacy and safety of TBLC in the diagnosis of peripheral lung diseases in the Endoscopy Center of Shanghai Pulmonary Hospital. Further, the application value of radial endobronchial ultrasound (R-EBUS) used to determine the optimal area for cryobiopsy was evaluated in this study. METHODS: In this retrospective study, the data of patients with unclarified ILDs or PPLs who underwent TBLC guided by R-EBUS between April 2020 and December 2021 at Shanghai Pulmonary Hospital in China were analyzed. RESULTS: A total of 137 patients [72 men, 65 women; median age, 52 years (range, 24-76 years)] were enrolled in the study. Out of the 137 patients included in the study, 123 (89.8%) were diagnosed after multidisciplinary discussions (MDDs), including 105 (85.4%) with ILD, 10 (8.1%) with tuberculosis, and 8 (6.5%) with a malignant tumor. Sixty-five (47.4%) patients had a definitive pathologic diagnosis through TBLC, including 54 (83.1%) with ILD, 5 (7.7%) with tuberculosis and 6 (9.2%) with malignant tumors. The overall pathological diagnosis rate was 47.4%. In addition to clarifying the blood supply situation of the candidate target, R-EBUS detected lesions in 44 (32.1%) patients. Mild and moderate bleeding occurred in 75.2% and 24.8% of patients, respectively. No cases of severe bleeding were observed. Pneumothorax occurred in 6 (4.4%) patients, of which 2 recovered without additional treatment, and 4 (66.7%) needed closed thoracic drainage. Hydropneumothorax and mediastinal emphysema occurred in one patient each. No patients died due to TBLC. CONCLUSIONS: R-EBUS-guided TBLC is safe and effective for the diagnosis of lung diseases, including ILDs and other PPLs. R-EBUS can guide cryobiopsy and avoid the potential risk of severe bleeding as well as radiation exposure. The pathological diagnosis rate of ILDs is relatively low, and MDD plays an important role in the diagnosis of ILDs.