Objective To compare the clinical efficacy of intravenous polymyxin B alone and intravenous drip combined with nebulized inhaled polymyxin B in treatment of patients with carbapenem-resistant organism (CRO) pneumonia. Methods The clinical data of 85 patients with CRO pneumonia admitted to the Intensive Care Unit of Nanjing Drum Tower Hospital from September 2020 to June 2023 were collected using a retrospective study. According to the different ways of administration of polymyxin B, the patients receiving polymyxin B intravenous drip therapy alone were included in group A, and the patients receiving polymyxin B intravenous drip therapy combined with nebulized inhalation therapy were included in group B. The therapeutic effective rate, bacterial clearance rate, 30-day all-cause mortality and the level of infection indexes before and after the use of medication were compared between the two groups. The occurrence of acute kidney injury during the use of drugs in the two groups was observed and recorded. Results The pathogenicity culture results showed that there was no statistically significant difference between the two groups (P=0.144). Serum procalcitonin and C-reactive protein were significantly lower in the two groups after drug administration compared with those before drug administration (both P<0.05). The therapeutic efficiency and bacterial clearance rate in group B were higher than those in group A (both P<0.05). There was no statistically significant difference in 30-day all-cause mortality between the two groups (P=0.664). And there was no statistically significant difference in the incidence of adverse reactions between the two groups (P=0.650). Conclusion When polymyxin B is used to treat patients with CRO pneumonia, the intravenous drip combined with nebulized inhalation regimen is superior to intravenous drip therapy alone and does not increase the risk of developing nephrotoxicity.