Ehlers-Danlos syndrome (EDS) is a group of hereditary diseases causing connective tissue fragility due to genetic abnormalities in collagen and its modifying enzymes. We report two surgical cases of pneumothorax associated with EDS. Case 1 was initial-onset left pneumothorax in a 43-year-old woman with a history of retinal detachment and multiple cavitary lesions of the bilateral lungs on preoperative imaging. Intraoperatively, air leakage was observed from the cavitary lesion of the left lower lobe, and wedge resection of the lung was performed. The lung tissue was extremely fragile, and additional air leakage was observed from both the grasped lung parenchyma and staple line. Additional stitches and biological tissue adhesive were needed to control the air leakage. The patient was diagnosed with classical EDS after the operation. Case 2 involved recurrent right pneumothorax in a 38-year-old woman. She had a history of perforation of the descending colon and was diagnosed with vascular EDS. Air leakage was observed from the cyst in the right upper lobe intraoperatively, and the cyst was sewn. Since the lung tissue was very fragile and another air leakage occurred from the grasped lung parenchyma, it was excised with an automatic suture device and covered with absorbent suture reinforcement. Parietal pleura scraping was added to promote intrathoracic adhesion. Although elastic fibers were pathologically maintained in the resected specimens of both cases, the lung tissues were extremely fragile. For patients with diagnosed or suspected EDS during pneumothorax surgery, it is essential to adopt protective measures that address the tissue fragility.