Background and purposeWe previously developed a new surgical method, namely, single-port inflatable mediastinoscopy simultaneous laparoscopic-assisted radical esophagectomy. The purpose of this study was to evaluate the effect of carbon dioxide inflation on respiration and circulation using this approach.MethodsFrom April 2018 to October 2020, 105 patients underwent this novel surgical approach. The changes in respiratory and circulatory functions were reported when the mediastinal pressure and pneumoperitoneum pressure were 10 and 12 mmHg, respectively. Data on blood loss, operative time, and postoperative complications were also collected.Results104 patients completed the operation successfully, except for 1 patient who was converted to thoracotomy because of intraoperative injury. During the operation, respectively, the heart rate, mean arterial pressure, central venous pressure, peak airway pressure, end-expiratory partial pressure of carbon dioxide and partial pressure of carbon dioxide increased in an admissibility range. The pH and oxygenation index decreased 1 h after inflation, but these values were all within a safe and acceptable range and restored to the baseline level after CO2 elimination. Postoperative complications included anastomotic fistula (8.6%), pleural effusion that needed to be treated (8.6%), chylothorax (0.9%), pneumonia (7.6%), arrhythmia (3.8%) and postoperative hoarseness (18.2%). There were no cases of perioperative death.ConclusionsWhen the inflation pressure in the mediastinum and abdomen was 10 mmHg and 12 mmHg, respectively, the inflation of carbon dioxide from single-port inflatable mediastinoscopy simultaneous laparoscopic-assisted radical esophagectomy did not cause serious changes in respiratory and circulatory function or increase perioperative complications.