A 77-year-old man was brought to our hospital because of secondary pneumothorax associated with idiopathic pulmonary fibrosis (IPF). After the initial successful treatment with thoracic drainage and autologous blood patch pleurodesis, he developed pneumothorax twice; each time, he was treated with the same procedure. He eventually developed chronic respiratory failure; as a result, long-term oxygen therapy was initiated. When he was hospitalized for the fourth time with pneumothorax, his condition did not improve with thoracic drainage and autologous blood patch pleurodesis. Neither surgery nor invasive pleurodesis could be performed because of the possible risk of acute exacerbation of IPF. Blood coagulation factor XIII was intravenously administered to the patient owing to its low activity. The air leakage ceased promptly, and the thoracic drain could be removed thereafter. Intravenous administration of blood coagulation factor XIII may be considered an effective treatment for intractable pneumothorax with interstitial pneumonia and IPF.