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Patients undergoing epigastric surgery at high altitudes are at increased risk of postoperative pulmonary complications (PPCs) due to hypobaric hypoxia and altered respiratory mechanics. This study aimed to determine whether a protective ventilation strategy combining driving pressure (ΔP) guidance and lung ultrasound (LUS) monitoring could reduce PPCs compared with conventional protective ventilation in patients undergoing epigastric surgery on the Tibetan Plateau(> 3500 m). In this randomized controlled trial, 152 adult patients scheduled for elective epigastric surgery were assigned to either conventional protective ventilation (n = 75) or ΔP-guided ventilation (n = 77). The conventional group received a tidal volume of 6 mL/kg predicted body weight, PEEP of 5 cmH2O, and a standard recruitment maneuver. The ΔP-guided group received the same tidal volume with individualized PEEP titration to minimize ΔP, combined with an LUS-guided recruitment maneuver. The primary outcome was the incidence of PPCs within seven days after surgery, assessed using the modified Kroenke severity score. Secondary outcomes included intraoperative ΔP, mechanical power, oxygenation, respiratory compliance, and hospital length of stay (assessed on postoperative days 1, 3, and 7). For each patient, the highest modified Kroenke score observed across the scheduled assessments within 7 days was used for analysis. The incidence of clinically significant PPCs (grade ≥ 2) was significantly lower in the ΔP-guided group than in the conventional group. Compared with conventional ventilation, ΔP-guided ventilation achieved lower driving pressure, higher individualized PEEP, improved oxygenation indices, and fewer cases of atelectasis. Mechanical power was modestly higher in the ΔP-guided group, while remaining within a low range in both groups. Hospital stay was shorter in the ΔP-guided group. ΔP-guided ventilation combined with LUS monitoring significantly reduced PPCs and improved intraoperative respiratory mechanics and oxygenation in patients undergoing epigastric surgery at high altitude. This strategy provides a physiologically informed approach to lung protection under hypobaric hypoxia. Trial registration: This trial was prospectively registered at the Chinese Clinical Trials Registry (ChiCTR) under the registration number ChiCTR2200057189 (02/03/2022).