Objective To compare the clinical efficacy of high-dose tigecycline (TGC) and polymyxin B (PMB) in the treatment of pulmonary infection due to carbapenem-resistant organism (CRO). Methods Clinical data of patients with CRO pulmonary infection and received PMB or high-dose TGC combined with other antimicrobial treatment regimens in Department of Critical Care Medicine of Xiangya Hospital, Central South University from January 2019 to March 2022 were analyzed retrospectively, including basic information, pathogen detection results, antimicrobial use regimen, clinical efficacy, 30-day mortality, bacterial clearance rate, etc. Results A total of 173 patients were included in analysis, with 103 in the TGC group and 70 in the PMB group. Compared with TGC group, PMB group had a higher score of acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) (25.0 vs 20.0, P<0.001), but clinical efficacy rates were not statistically different (67.1% vs 52.4%, P=0.054). Stratified analysis revealed that when the APACHE Ⅱ score was ≥15 points, compared with TGC group (n=78), PMB group (n=66) had a higher APACHE Ⅱ score (27.0 vs 22.0, P=0.005) and a higher clinical efficacy rate (66.7% vs 47.4%, P=0.020). After adjusting confounding factors through logistic regression analysis, it was found that PMB treatment was a protective factor for clinical efficacy rate compared with TGC treatment. Conclusion For treating pulmonary infection caused by CRO in patients, PMB-based treatment regimen has a significant protective effect on the clinical efficacy rate compared with the high-dose TGC-based treatment regimen.