Thoracic epidural anesthesia (TEA) is associated with a knowledge gap regarding its mechanisms in lung protection and reduction of postoperative pulmonary complications (PPCs). Driving pressure (ΔP), an alternative indicator of alveolar strain, is closely linked to reduced PPCs with lower ΔP values. We aim to investigate whether TEA contributes to lung protection by lowering ΔP during mechanical ventilation.In this prospective, randomized, patient and evaluator-blinded parallel study, adult patients scheduled for elective major upper abdominal surgery were assigned to either the TEA group with combined thoracic epidural anesthesia and general anesthesia (TEA-GA) (n = 30) or the control group with only general anesthesia (GA) (n = 30).The primary outcome was the minimum ΔP determined based on positive end-expiratory pressure (PEEP) after intubation. Secondary outcomes included the incidence of PPCs within seven days, the minimum ΔP at various time points, blood gas analysis, intensive care unit (ICU) admission rates, length of hospital stay, and 30-day mortality rate.The TEA group had a significantly lower minimum ΔP titrated based on PEEP compared to the control group (11.23 ± 2.19 cmH2O vs. 12.67 ± 2.70 cmH2O; P = 0.028). Multivariate linear regression analysis showed that intraoperative TEA application (compared with its absence; unstandardized beta coefficient (B) = -1.289; P = 0.008) significantly correlated with ΔP. The incidence of PPCs did not differ significantly between the two groups (8 of 30 [26.7%] vs. 12 of 30 [40%]; P = 0.273), but the incidence of atelectasis in the TEA group was significantly lower than in the control group (5 of 30 [16.7%] vs. 12 of 30 [40.7%]; P = 0.012). Multivariate logistic regression analysis indicated that ΔP was the only variable significantly associated with PPCs (Adjusted Odds Ratio [OR] = 2.190; 95% Confidence Interval [CI]: 1.300 to 3.689; P = 0.003).Compared to GA, TEA-GA can reduce intraoperative ΔP in patients undergoing major upper abdominal surgery, especially those undergoing laparoscopic surgery. However, compared to GA combined with ΔP-guided ventilation, TEA-GA combined with ΔP-guided ventilation does not reduce the risk of PPCs. There was no significant difference in the total use of various vasoactive drugs between the two groups.This study was registered in the Chinese Clinical Trial Registry (registration number ChiCTR2300068778 date of registration February 28, 2023).© 2024. The Author(s).