Abstract: Background Laparoscopic CO2 pneumoperitoneum can elevate the closing pressure of alveoli during expiration. If the PEEP applied is insufficient, it can lead to an increase in the volume of lung collapse during mechanical ventilation, thereby inducing atelectasis and barotrauma. Therefore, a higher level of individualized PEEP is required to maintain alveolar open during expiration and reduce lung injury during CO2 pneumoperitoneum. However, there is no consensus on the optimal positive endexpiratory pressure (PEEP) during pneumoperitoneum. Objective To investigate the impact of individualized PEEP setting guided by pneumoperitoneum pressure on the incidence of hypoxemia from 30 minutes after extubation to 3 days postoperatively in elderly patients undergoing abdominal laparoscopic surgery. Methods A total of 100 elderly patients undergoing elective general anesthesia for abdominal laparoscopic surgery in the First Medical Center of Chinese PLA General Hospital from October 2023 to April 2024 were enrolled. The subjects were randomly allocated into two groups using a random number table method: the pneumoperitoneum pressure-guided PEEP group (P group, n=50) and the traditional PEEP group (C group, n=50). During mechanical ventilation, a PEEP level (cmH2O) equaling to the pneumoperitoneum pressure (mmHg) was used in the P group during the pneumoperitoneum period, while the C group used 5 cmH2O of PEEP throughout the procedure. The primary outcome was the incidence of hypoxemia from 30 minutes after extubation to 3 days postoperatively. The secondary outcomes included driving pressure, plateau pressure, compliance of respiratory system, oxygenation index (PaO2/FiO2), and hemodynamic data at 10 minutes after induction (T1), 10 minutes after pneumoperitoneum (T2), and 60 minutes after pneumoperitoneum (T3). Results A total of 97 patients were included in the final analysis. Among them, 49 patients were included in group P, with an average age of (67.9 ± 6.5) years; 48 patients were included in group C, with an average age of (67.5 ± 4.8) years. There was no statistically significant difference in patient demographics between the two groups (P > 0.05). The incidence of postoperative hypoxemia was significantly lower in the P group than that of the C group (10.4% 5/48 vs 30.6% 15/49, P=0.022). Driving pressure and dynamic compliance at 10 and 60 minutes after pneumoperitoneum were significantly better in the P group when compared to the C group. The PaO2/FiO2 after pneumoperitoneum deflation in the P group was significantly higher than the C group. There were no significant differences in the use of vasopressors or total fluid infusion between the groups. Conclusion Individualized PEEP setting guided by pneumoperitoneum pressure can reduce the incidence of postoperative hypoxemia, improve respiratory mechanics and PaO2/FiO2 during the surgery.