OBJECTIVE: Prolonged air leak due to residual air space after lung resection is a main challenge. To date, few surgical options have been described to prevent this complication. The aim of this study is to investigate the safety and the efficacy of intraoperative phrenic nerve infiltration with long-acting anesthetics in producing transient hemidiaphragm paralysis in patients at high risk for prolonged air leak, thus improving pulmonary expansion after surgery and reducing air leaks, while controlling postoperative pain. METHODS: Between January 2021 and 2023, 65 consecutive patients at risk for prolonged air leak (defined in accordance with "2019 Society of Thoracic Surgery score criteria of prolonged air leak") who underwent lung resection (lobectomy or anatomic segmentectomy) for malignancy were prospectively included in the study. They were randomly (1:2 ratio) assigned to receive (group A, 22 patients) intraoperative phrenic nerve infiltration with ropivacaine 10 mg/mL in the peri-neurotic fat on the pericardium or not to receive intraoperative phrenic nerve infiltration (group B, 43 patients). Five patients in group B were excluded because they did not undergo anatomic resection. Data on pulmonary reexpansion, prolonged air leaks, pain at 24 and 72 hours postsurgery, referred shoulder pain, length of hospital stay, and length of chest tube permanence were collected and compared. RESULTS: Hemidiaphragm elevation ( CONCLUSIONS: This is the first study to investigate 2 combined effects of phrenic nerve anesthetic infiltration (hemidiaphragm elevation and pain control), with potential enhancement of a patient's recovery after surgery. Intraoperative phrenic nerve infiltration in patients with a risk for prolonged air leak appears to be a safe and effective clinical practice to improve pulmonary expansion in this set of patients, reducing postoperative air leak. This result is associated with an additional improvement in pain control, especially for shoulder pain.