Objectives In this study, we examined whether (1) positive end-expiratory pressure (PEEP) has a protective effect on the risk of major postoperative respiratory complications in a cohort of patients undergoing major abdominal surgeries and craniotomies, and (2) the effect of PEEP is differed by surgery type. Background Protective mechanical ventilation with lower tidal volumes and PEEP reduces compounded postoperative complications after abdominal surgery. However, data regarding the use of intraoperative PEEP is conflicting. Methods In this observational study, we included 5915 major abdominal surgery patients and 5063 craniotomy patients. Analysis was performed using multivariable logistic regression. The primary outcome was a composite of major postoperative respiratory complications (respiratory failure, reintubation, pulmonary edema, and pneumonia) within 3 days of surgery. Results Within the entire study population (major abdominal surgeries and craniotomies), we found an association between application of PEEP ≥5cmH2O and a decreased risk of postoperative respiratory complications compared with PEEP <5cmH2O. Application of PEEP >5cmH2O was associated with a significant lower odds of respiratory complications in patients undergoing major abdominal surgery (odds ratio 0.53, 95% confidence interval 0.39 – 0.72), effects that translated to deceased hospital length of stay [median hospital length of stay : 6 days (4–9 days), incidence rate ratios for each additional day: 0.91 (0.84 - 0.98)], whereas PEEP >5cmH2O was not significantly associated with reduced odds of respiratory complications or hospital length of stay in patients undergoing craniotomy. Conclusions The protective effects of PEEP are procedure specific with meaningful effects observed in patients undergoing major abdominal surgery. Our data suggest that default mechanical ventilator settings should include PEEP of 5–10cmH2O during major abdominal surgery.