Introduction: Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene. Recurrent respiratory infections are a common problem, and patients receive frequent antibiotics. Treatment of CF involves both symptomatic and underlying disease-targeting therapies. Elexacaftor/tezacaftor/ivacaftor (ETI), a disease-targeting therapy, combines two correctors and a potentiator to increase functioning of the CFTR channel. With better functioning channels, symptomatic improvement is expected in the form of decreased respiratory infections. Objective: To evaluate the change in antibiotic use following the initiation of ETI therapy in pediatric patients. Methods: This is a single-center, retrospective chart review conducted at Nationwide Children’s Hospital (NCH) in Columbus, Ohio. Patients served as self-controls, compared before and after initiating ETI. The primary outcome was change in antibiotic days per patient-year. Secondary outcomes included change in specific antibiotic use, enteral versus intravenous therapy, and different classes of antibiotics. The study was approved by the NCH IRB. Results: 139 patients were included. The median antibiotic days per patient-year was 17 days pre-ETI and 6 days post-ETI (p<0.001). There was a significant decrease in antibiotic days per patient-year for intravenous antibiotics, enteral antibiotics, intravenous vancomycin, linezolid/tedizolid, anti-methicillin-resistant Staphylococcus aureus (MRSA) tetracyclines, other anti-MRSA medications (clindamycin and sulfamethoxazole-trimethoprim), aminoglycosides, anti- Pseudomonas aeruginosa (PSAE) beta-lactams, and fluoroquinolones. There was no significant difference in carbapenems or non-anti-PSAE beta-lactams. Conclusion: ETI therapy was associated with decreased antibiotic days for many therapeutic classes of both enteral and intravenous antibiotics.