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Background: This study aimed to assess the efficacy of ceftolozane-tazobactam (C/T) for treating infections due to Pseudomonas aeruginosa (P. aeruginosa) in critically ill patients., Patients and Methods: A multicenter, retrospective and observational study was conducted in critically ill patients receiving different C/T dosages and antibiotic combinations for P. aeruginosa infections. Demographic data, localisation and severity of infection, clinical and microbiological outcome, and mortality were evaluated., Results: Ninety-five patients received C/T for P. aeruginosa serious infections. The main infections were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteraemia (10.5%). Forty-six episodes were treated with high-dose C/T (3 g every 8 hours) and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics. Sixty-eight (71.6%) patients presented a favourable clinical response. Microbiological eradication was documented in 42.1% (40/95) of the episodes. The global ICU mortality was 36.5%. Univariate analysis showed that 30-day mortality was significantly associated (P < 0.05) with Charlson Index at ICU admission and the need of life-supporting therapies., Conclusions: C/T appeared to be an effective therapy for severe infections due to P. aeruginosa in critically ill patients. Mortality was mainly related to the severity of the infection. No benefit was observed with high-dose C/T or combination therapy with other antibiotics., (Copyright © 2021. Published by Elsevier Ltd.)