Pseudomonas aeruginosa is a commonly isolated pathogen in adults with cystic fibrosis (CF). Antimicrobial resistance is an escalating problem due to chronic colonization and frequent antimicrobial exposure. Ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) exhibit promising activity against antimicrobial resistant organisms, including P. aeruginosa. A retrospective review was conducted comparing the in vitro activities of C/T and CZA against 42 P. aeruginosa isolates from the respiratory tract of 32 adults with CF. The first isolate per patient per year that underwent susceptibility testing for C/T, CZA, and colistin was included. C/T was more susceptible than CZA (60% versus 43%). Thirty-eight (90%) isolates were considered highly drug resistant and demonstrated higher C/T susceptibilities compared to CZA (55% versus 45%). These results suggest using C/T while awaiting susceptibilities when standard antipseudomonal agents cannot be used.