Objective To investigate the therapeutic efficacy and side effect of polymyxin B-based combination therapy for the treatment of severe pneumonia caused by extensively drug-resistant Acinetobacter baumanii (XDR-AB)and XDR Klebsiella pneumoniae (XDR-KP), and provide support for clinicians in the treatment of severe pneumonia caused by XDR bacteria. Methods Patients who were admitted to the department of critical care medicine of a hospital from April 1, 2018 to April 30, 2019 and received polymyxin B-based combination therapy for pathogenic confirmed extensively XDR-AB and XDR-KP severe pneumonia were selected as research objects. Therapeutic efficacy, microbial treatment efficacy, liver and kidney function damage, pigmentation of skin and other side effects were observed. Results A total of 24 patients with XDR bacterial severe pneumonia were selected, 26 times of treatment were conducted, clinical therapeutic effective rate was 73.1%. A total of 139 sputum cultures were sent for examination, 138 times of antimicrobial susceptibility results showed that bacteria were sensitive to polymyxin B (MIC 0.5-1 μg/mL), only one time was resistant to polymyxin B (MIC=8 μg/mL). Bacterial clearance rate of Acinetobacter baumannii was higher than that of Klebsiella pneumoniae (60.9% vs 7.7%), difference was statistically significant (P=0.004). Incidence of acute kidney injury (AKI) was 42.3%, only one patient ended treatment in advance because of renal function damage; renal function of the survival patients with AKI (survival rate 60.0%) all recovered to normal, incidence of pigmentation of skin was 20.8%, drug-related liver damage and other complications were not found. Conclusion Efficacy of polymyxin B-based combination therapy for XDR-AB and XDR-KP severe pneumonia is high, although strains are sensitive to polymyxin B, bacterial clearance rate is relatively low, polymyxin B has certain nephrotoxicity, and the renal damage of patients who survived after active treatment of primary disease is generally reversible.