Background: The aim of this study is to evaluate cardiovascular and respiratory effects of intrathoracic pressure overshoot (higher than insufflation pressure) in patients who underwent thoracoscopic esophagectomy with carbon dioxide (CO2) pneumothorax.Methods: This prospective research included 200 patients who were scheduled for esophagectomy. The patients were randomly divided into the Stryker insufflator (STR) group and the Storz insufflator (STO) group. We recorded the changes of intrathoracic pressure, cardiopulmonary function and recovery time, and compared these indexes between the two groups.Results: We found that during the artificial pneumothorax, intrathoracic pressure overshoot occurred in both the STR group (8.9 mmHg, 38 times per hour) and the STO group (9.8 mmHg, 32 times per hour). The recorded maximum intrathoracic pressures were up to 58 mmHg in the STR group and 51 mmHg in the STO group. The average duration of intrathoracic pressure overshoot was significantly longer in the STR group (5.3 ± 0.86 s) vs. the STO group (1.2 ± 0.31 s). During intrathoracic pressure overshoot, a greater reduction in systolic blood pressure (SBP) (5.6 mmHg vs 1.1 mmHg), a higher elevation in airway peak pressure (4.8 ± 1.17 cmH2O vs 0.9 ± 0.41 cmH2O), and a larger increase in CVP (8.2 ± 2.86 cmH2O vs 4.9 ± 2.35 cmH2O) were observed in the STR group than in the STO group. Vasopressors were also applied more frequently in the STR group than in the STO group (68% vs 43%, P < 0.01). The reduction of SBP caused by thoracic pressure overshoot was significantly correlated with the duration of overshoot (R = 0.76) while not with the maximum overshoot pressure.Conclusion: Intrathoracic pressure overshoot can occur during thoracoscopic surgery with artificial CO2 pneumothorax and may lead to cardiovascular adverse effects which highly depend on the duration of the pressure overshoot.