Treatment with ceftolozane–tazobactam resulted in higher rates of clinical success compared with ceftazidime–avibactam for invasive infections due to multidrug-resistant P aeruginosa. Differences were driven by improved response rates for patients with pneumonia who were treated with ceftolozane–tazobactam. There were no significant differences between study groups with respect to all-cause mortality; treatment-emergent resistance was common with both agents.