To describe the largest clinical experience using ceftolozane-tazobactam (C/T) for treatment of different type of Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy from June 2016 to March 2018. All adult patients treated with at least 4 days of C/T were enrolled. A successful clinical outcome was defined as complete resolution of clinical signs and symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin structure infections (30.8%), complicated UTI (13.8%), complicated IAI (12.8%), bone infections (8.9%) and primary bacteraemia (7.9%). Almost half of P.aeruginosa strains were XDR (51%), with 78% of the isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (34.6%). When used as second or later line, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P.aeuruginosa strain and clinical failure of previous therapy. Concomitant antibiotics was reported in 35% of patients. C/T doses were 1.5 grams/8h in 70 patients (69.3%) and 3 grams/8h in 31 patients (30.7%); the median duration of C/T therapy was 14 days. The overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or those receiving continuous renal replacement therapy. Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the type of infection. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving continuous renal replacement therapy.