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Background: No clear evidence supports the use of cefiderocol as first line treatment in A. baumannii infections. Methods: We conducted an observational retrospective/prospective multicenter study including all patients >18 years with carbapenem-resistant A. baumannii(CRAB) infections treated with cefiderocol, from June 1 2021 to October 30 2022. Primary endpoint was in-hospital mortality, secondary end-points the clinical and microbiological response at 7 days and at the end of treatment. Furthermore, we compared the clinical and microbiological outcomes among patients who received cefiderocol in monotherapy or in combination. Results: Forty infections were included [mean age 65 years (SD +16.3), 75% males, 90% with hospital-acquired infections and 70% showing sepsis or septic shock]. The most common infections included unknown source or catheter-related bacteremia (45%) and pneumonia (40%). We observed at 7 days and at the end of therapy a rate of microbiological failure of 20% and 10%, respectively, and of clinical failure of 47.5% and 32.5%, respectively; the in-hospital mortality rate was 50%. At multivariate analysis McCabe score of 2-3 and clinical failure at 7 days of treatment were the only independent predictors of in-hospital mortality. Comparing monotherapy (used in 72.5%) vs. combination therapy (used in 27.5%), no differences were observed in mortality (51.7 vs 45.5%) and clinical (41.4 vs 63.7%) or microbiological failure (24.1 vs 9.1%). Conclusions: The findings of this study reinforce the effectiveness of cefiderocol in CRAB infections, also as monotherapy. However, prospective multicenter studies with larger sample sizes and a control group treated with standard of care are needed to identify the best treatment for CRAB infections.