Objective <p>The efficacy and safety of colistin sulfate (CS) and polymyxin B sulfate (PBS) were evaluated in critically ill patients with carbapenem-resistant Gram-negative bacteria (CR-GNB) infections, and predictors affecting clinical outcomes were identified.</p> Methods <p>CR-GNB-infected ICU patients treated between February 2023 and December 2024 were retrospectively analyzed. Patients were grouped according to treatment, and inverse probability of treatment weighting (IPTW) was applied to balance confounding factors and compare clinical efficacy, microbiological clearance rates, and safety between groups. Prespecified subgroup analyses by pathogen type were conducted, with doubly robust estimation applied in the CRAB subgroup. Differences in trough concentrations (C_min) were evaluated among clinical efficacy groups, acute kidney injury (AKI) groups, and mortality groups. Univariate and multivariate analyses were performed to identify prognostic factors for efficacy and mortality.</p> Results <p>The CS group and the PBS group have 85 and 78 patients, respectively. Following IPTW adjustment for indication-based confounders, the two groups were well-balanced in baseline demographic characteristics, and showed no significant differences in clinical and microbiological efficacy, or in 14-day and 28-day mortality rates. However, the PBS group exhibited a significantly higher proportion of severe AKI (stages II and III) compared to the CS group (OR = 6.865, 95% CI: 1.463–32.221, <i>P</i> = 0.015).In prespecified subgroup analyses, the risks of both overall AKI (OR = 4.84, 95% CI 1.45–16.15, <i>P</i> = 0.011) and severe AKI (OR = 7.63, 95% CI 1.57–36.97, <i>P</i> = 0.012) were significantly elevated with PBS in patients with CRAB infection, with a significant treatment-by-pathogen interaction. No significant differences in C_min were observed across the clinical efficacy groups, AKI groups, and mortality groups. Multivariable analysis showed that in the CS group, the use of vasoactive drugs was an independent risk factor for poor clinical efficacy and 28-day mortality; In the PBS group, CRAB infection and age were independent risk factors for 28-day mortality, whereas vasoactive drug use was an independent risk factor for poor clinical efficacy, and loading dose administration served as an independent protective factor for clinical efficacy.</p> Conclusions <p>CS and PBS showed comparable clinical and microbiological efficacy. PBS was associated with a higher risk of severe AKI in the overall cohort. Notably, within the CRAB subgroup, PBS showed significantly elevated risks for both overall and severe AKI.</p>