BackgroundIn patients with interstitial lung diseases (ILD), histopathological input is often required to obtain a diagnosis. Surgical lung biopsy (SLB) is considered the reference standard, but many patients are clinically unfit to undergo this invasive procedure, and adverse events, length of hospitalization and costs are considerable. This guideline provides evidence-based clinical practice recommendations for the role of transbronchial lung cryobiopsy (TBLC) in obtaining tissue-based diagnosis in patients with undiagnosed ILD.Materials and methodsThe European Respiratory Society task force consisted of clinical experts in the field of ILD and/or TBLC, and methodological experts. Four PICO questions and two narrative questions were formulated. Systematic literature searches were performed in Medline and Embase (up to June 2021). GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology was applied.ResultsIn patients with undiagnosed ILD and an indication to obtain histopathological data: 1) TBLC is suggested as replacement test in patients considered eligible to undergo SLB, 2) TBLC is suggested in patients not considered eligible to undergo SLB, 3) SLB is suggested as add-on test in patients with a non-informative TBLC, 4) no recommendation is made for or against second TBLC in patients with a non-informative TBLC, and 5) TBLC-operators should undergo training, but no recommendation is made for the type of training required.ConclusionTBLC provides important diagnostic information in patients with undiagnosed ILD. Diagnostic yield is lower compared to SLB, at reduced serious adverse events and length of hospitalization. Certainty of the evidence is mostly “very low”.