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The gold standard for the histological diagnosis of interstitial lung diseases (ILD) is an open lung biopsy (OLB). Tissue samples obtained by forceps transbronchial lung biopsies (TBB) are usually too small. We aim to evaluate the efficacy and safety of cryo-TBB for the diagnosis of ILD and to explore its role as substitute for OLB.Seventy-five patients (mean age 56.2 years) with clinical and radiological features suggestive of ILD underwent cryo-TBB under moderate sedation. The diagnostic contribution on the work-up of suspected ILD was assessed.No major complications occurred during cryo-TBB procedures. The mean cross-sectional area of the biopsy specimen obtained was 9 mm2 with an average of 70% alveolated tissue. The most common pathological diagnoses were idiopathic nonspecific interstitial pneumonitis (n = 22), cryptogenic organizing pneumonia (n = 11) and usual interstitial pneumonitis (n = 7). There were three patients of pulmonary Langerhans cell histiocytosis and one patient of pulmonary lymphangioleiomyomatosis. A definite and probable clinicopathological consensus diagnosis was possible in 70% and 28% of patients, respectively. In only 2% of patients' diagnosis could not be established.Cryo-TBB is a safe and effective minimally invasive modality for the diagnosis of ILD. No OLB is needed in the majority of patients.Cryo-transbronchial biopsy provides diagnostic material that enables a histological diagnosis in patients with interstitial lung diseases and obviates the need for open lung biopsy in the majority of patients.