Background We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI). Materials/methods Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW). Results Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p  = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p  < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL ( p  = 0.008 and p  = 0.0008, respectively). Increment of CCI ( p  = 0.005), ICU ( p  = 0.025), SARS-CoV2 ( p  = 0.006) and ECMO ( p  < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival. Conclusions CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided. Key summary points Increasing real-life data support the clinical effectiveness and safety of cefiderocol (CFDC) for carbapenem resistant Acinetobacter baumannii (CRAB) infections. We investigated CFDC in comparison with colistin (COL) for the treatment of CRAB bloodstream infections (BSI). Clinical cure was higher in CFDC than COL group. Patients with hospital acquired/ventilator-associated pneumonia treated with CFDC had a statistically significant lower 30-d mortality and higher clinical cure than those treated with COL. Adverse events were more frequent in COL than in CFDC-group. CFDC could be an effective and safe treatment option for CRAB BSI, especially in patients with HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided.