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Introduction: Transbronchial lung cryobiopsy has been recommended as an acceptable alternative to surgical approach for making a histopathological diagnosis in patients with interstitial lung disease (ILD) of undetermined type. In limited diseases (especially if distributed along the subpleural region), sampling the specific area in which the pathological process is more represented could be challenging. Aim of the study was to determine the potential benefit of utilizing cone-beam computed tomography-guided cryobiopsy in patients with limited extent of ILD on CT scan and determine the single impact of each sequential biopsy progressively increasing the total number of biopsies. Methods: This study is a prospective analysis of patients with undetermined ILD and CT scan extent <15% undergoing cone-beam CT-guided cryobiopsy. Each biopsy sample was collected and processed individually and pathologic interpretations were performed sequentially with the pathologist reformulating a new report with the addition of each sample (cumulative yield). Results: Thirty six patients were enrolled. Pathological diagnostic yield was >90%, with almost 80% of diagnostic samples being the first one; when a second biopsy was performed, mean diagnostic yield increased with only a moderately significant difference. No severe adverse events were observed; pneumothorax was documented in 27.8% of the cases. Conclusion: Sequential individual collection and pathologic interpretation of each biopsy sample has confirmed the possibility of obtaining a diagnostic specimen at the first pass if transbronchial cryobiopsy is performed under cone-beam CT. [ABSTRACT FROM AUTHOR]