Introduction: Multidrug-resistant Pseudomonas aeruginosa isolates have multiple resistance mechanisms, and there are insufficient therapeutic options to target them. Ceftolozane-tazobactam is a novel antipseudomonal agent that contains a combination of an oxyimino-aminothiazolyl cephalosporin (ceftolozane) and a β-lactamase inhibitor (tazobactam). Methods: A single-center retrospective observational study between January 2017 and December 2018 for patients who had been diagnosed with carbapenem-resistant P aeruginosa infections and treated with ceftolozane-tazobactam for more than 72 hours. We assessed clinical success based on microbiological clearance as well as the clinical resolution of signs and symptoms of infection. Results: A total of 19 patients fit the inclusion criteria, with a median age was 57 years, and 53% were female. The types of infections were nosocomial pneumonia, acute bacterial skin, and skin structure infections; complicated intra-abdominal infections; and central line–associated bloodstream infections. All of the isolates were resistant to both meropenem and imipenem. The duration of therapy was variable (average of 14 days). At day 14 of starting ceftolozane-tazobactam, 18 of 19 patients had a resolution of signs and symptoms of the infection. Only 14 of 19 patients (74%) had proven microbiological eradication observed at the end of therapy. During therapy, there was no adverse event secondary to ceftolozane-tazobactam, and no Clostridium difficile infection was identified. The 30-day mortality rate was 21% (4/19). Conclusions: Multidrug-resistant P aeruginosa infection is associated with high mortality, which would potentially be improved using a new antibiotic such as ceftolozane-tazobactam. Studies are required to explain the role of combination therapy, define adequate dosing, and identify the proper duration of treatment.