Background <p>Ventilator-induced lung injury caused by mechanical ventilation under general anesthesia as well as CO₂ pneumoperitoneum and special positions for laparoscopy may increase the risk of postoperative pulmonary complications (PPCs). Lung protective ventilation under general anesthesia is advised by the guidelines to lower the risk of PPCs in surgical patients. However, there is considerable controversy about the optimal level of positive end-expiratory pressure (PEEP) and how to set it. Driving pressure reflects the overall respiratory stress and high driving pressure is an independent risk factor for PPCs. The purpose of this study is to explore whether driving pressure-guided individualized PEEP ventilation can lower the incidence of postoperative atelectasis by improving respiratory mechanics during laparoscopic surgery consequently lowering the incidence of PPCs compared with the traditional fixed PEEP ventilation strategy.</p> Methods <p>The study will be a single-center, prospective, randomized controlled clinical study. A total of 106 adult patients with medium-to-high-risk PPCs undergoing laparoscopic surgery for more than 2&#xa0;h will be randomly assigned in a 1:1 ratio to receive an individualized PEEP guided by minimum driving pressure (group D) or a fixed PEEP of 5 cmH₂O (group C). Patients in group C will maintain a PEEP of 5 cmH₂O throughout the whole process, and patients in group D will be administered individualized PEEP after the start of pneumoperitoneum to achieve minimum driving pressure until the end of the operation. The primary outcome is the LUS score at 24&#xa0;h postoperatively. The secondary outcomes are the LUS scores at other time points, intraoperative respiratory mechanics and oxygenation index, incidence and specific types of PPCs at 7&#xa0;days postoperatively.</p> Discussion <p>This study will better evaluate the effect of individualized PEEP application guided by driving pressure on the incidence of postoperative atelectasis based on ultrasound assessment consequently the incidence of PPCs in patients undergoing prolonged laparoscopic surgery. The results may provide a clinical evidence for optimizing perioperative lung protection strategies.</p> Trial registration <p><a href="http://www.chictr.org.cn">www.chictr.org.cn</a> ChiCTR2300079041. Registered on December 25, 2023.</p>