Postoperative pulmonary complications (PPCs) are a major cause of postoperative morbidity, mortality, and longer hospital stays. Expectorants are widely used during the perioperative period to reduce PPCs. This study aimed to compare the clinical effectiveness between ambroxol (AMB) and N-acetylcysteine (NAC) in patients undergoing surgery. A multicenter, retrospective cohort study was conducted using deidentified medical records from hospital information system. Between July 1, 2015, and November 30, 2017, patients aged ≥18 years, who received intravenous AMB or nebulized NAC as the only expectorant therapy for >3 days during their hospitalization for thoracic, abdominal, and neurosurgery, were included in this study. The clinical outcomes were evaluated, and propensity score matching was used to adjust significant differences between 2 groups. A total of 4025 cases in the AMB group and 2062 in NAC group after propensity score matching were identified. The incidence of PPCs (13.9% vs 11.6%; P = .013), postoperative sputum suction (17.2% vs 8.0%; P < .001), intensive care unit admission after surgery (25.1% vs 22.5%; P = .024), and postoperative mechanical ventilation (22.3% versus 17.5%; P < .001) in the AMB group were all significantly higher than those in the NAC group. This study suggested that patients treated with NAC during the perioperative period had a significantly lower risk of PPCs. However, further prospective study is needed to ensure the replicability of our findings.