Objective <p>To compare the clinical efficacy and safety of intravenous polymyxin B versus the combination of intravenous and nebulized polymyxin B for treating carbapenem-resistant gram-negative bacilli hospital-acquired pneumonia (CRGNB-HAP), and to explore the risk factors affecting 28-day all-cause mortality.</p> Method <p>Our retrospective analysis was conducted on data from CRGNB-HAP patients treated in the intensive care unit (ICU) with either intravenous polymyxin B alone or in conjunction with nebulized polymyxin B between November 28, 2018 and May 6, 2024. The primary endpoint was 28-day all-cause mortality, while safety outcomes were also assessed. Logistic regression analysis was utilized to identify the risk factors associated with 28-day all-cause mortality.</p> Result <p>A total of 82 CRGNB-HAP patients were enrolled, including 38 patients in the intravenous plus nebulized (IV + NL) polymyxin B group and 44 patients in the intravenous (IV) polymyxin B group. The 28-day mortality rate of the IV + NL polymyxin B group was significantly lower than that of the IV polymyxin B group (23.7% vs 61.4%, p &lt; 0.001), and there was no statistically significant difference in the incidence of acute kidney injury between the two groups. Multivariate logistic regression analysis indicated that IV + NL polymyxin B administration was a significant factor in reducing the 28-day mortality rate of CRGNB-HAP patients.</p> Conclusion <p>Our study found that intravenous combined with nebulized polymyxin B therapy is superior to intravenous monotherapy in the treatment of CRGNB-HAP, resulting in reduced 28-day mortality without increasing renal toxicity.</p>