Background: Transbronchial lung cryobiopsy (TBLC) is an emerging technique in the diagnostic approach to diffuse parenchymal lung diseases. However, the role of TBLC in smoking-related Interstitial Lung Diseases (ILDs) is still under discussion. Objectives: The aim of the present study was to describe our experience with TBLC in diagnostic work-up of patients with smoking-related ILDs. Method: We retrospectively reviewed data of patients evaluated in a tertiary hospital ILDs outpatient clinic, who underwent TBLC, from September 2014 to December 2019. TBLC was performed in accordance with the 2018 expert statement from the Cryobiopsy Working Group. Results: Forty-five patients (25 men [55.6%]) with a mean age of 53.9 years [SD, 9.1] were included. The most frequent radiological pattern was ground glass opacity (42 patients). TBLC was performed in different segments of the same lobe in 38 patients and in two lobes in 7 patients. The mean maximal diameter of the samples was 5.2 mm (range, 3–16 mm [SD 2.0]). Pneumothorax occurred in seven patients (15%) and moderate bleeding occurred in one patient. A specific pathological diagnosis was achieved in 43 of 45 patients. The most frequent histopathologic pattern found was desquamative interstitial pneumonia (33 patients), followed by smoking-related interstitial fibrosis (7 patients), respiratory bronchiolitis - ILD (1 patient) and pulmonary Langerhans cell histiocytosis (1 patient). Two patients had alternative diagnosis (Pneumoconiosis and Interstitial Pneumonia with unspecific features) and one patient had normal lung parenchyma. A definitive multidisciplinary team (MDT) diagnosis was reached in 95.5% (43 of 45 cases). Two patients were submitted to additional diagnostic techniques. Conclusions: The results from this series support TBLC as a safe procedure with a meaningful diagnostic value in the context of a MDT approach of smoking-related ILDs.