Background: The use of a transbronchial lung cryobiopsy (TBLC) is increasing as a diagnostic method of interstitial lung diseases (ILD). This study aimed to evaluate risk factors associated with clinically significant complications of TBLC in ILD patients. Methods: Patients referred to Kuopio or Tampere university hospitals, in Finland, for a suspected ILD were included. The TBLC was performed in an outpatient setting for 100 patients. Patients were mechanically ventilated in general anesthesia. Fluoroscopy guidance and prophylactic bronchial balloon were used. Complications, such as bleeding, pneumothorax, infections, and mortality were recorded. Moderate or serious bleeding, pneumothorax, or death ≤90 days were defined as clinically significant complications. A multivariable model was created to assess clinically significant complications. Results: The extent of traction bronchiectasis (Odds ratio [OR] 1.30, Confidence interval [CI] 1.03–1.65, p = 0.027) and young age (OR 7.96, CI 2.32–27.3, p = 0.001) were associated with the risk of clinically significant complications whereas the use of oral corticosteroids ≤30 days before the TBLC (OR 3.65, CI 0.911–14.6, p = 0.068) did not quite reach statistical significance. A history of serious cough was associated with the risk of pneumothorax (OR 4.18, CI 1.10–16.0, p = 0.036). Procedure associated mortality ≤90 days was 1%. Conclusion: The extent of traction bronchiectasis on HRCT and young age were associated with the risk of clinically significant complications whereas oral corticosteroid use did not quite reach statistical significance. A history of serious cough was associated with the risk of clinically significant pneumothorax.