For a study, pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) were related to morbidity. The study aimed to compare clinical results of single versus double antipseudomonal antibiotic use for PEx treatment. Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were considered if hospitalized between 2007 and 2018 and 6–21 years of age. Regression modeling accounting for repeated measures was used. Among 10,660 PwCF in the dataset, analysis of 2,578 PEx from 1,080 PwCF were done, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. The study determined no contrast between PEx treated with 1 vs 2 IV antipseudomonal antibiotics either in change between pre and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (–0.84%, [95% CI –2.25, 0.56]; P=0.24), odds of returning to greater than or equal to 90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; P=0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; P=0.69). The use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not related to higher improvements in measured respiratory and clinical results compared to treatment with 1 IV antipseudomonal antibiotic.