Pulmonary exacerbations (PExs) are associated with significant morbidity in people with cystic fibrosis (CF). Severe PExs are treated with intravenous antibiotics, including tobramycin. CF care guidelines recommend continuing chronic maintenance medications during PEx treatment. Azithromycin (AZM) is one of the most widely prescribed chronic medications for CF in the United States. Recent evidence has identified a potential antagonistic relationship between AZM and tobramycin. To determine whether, among PEx treated with intravenous tobramycin, concomitant AZM use is associated with worse clinical outcomes. Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System (CFFPR-PHIS)-linked dataset. People with CF age 6-21 years were included if they were hospitalized between 2006 and 2016 for a PEx. Inverse probability of treatment weighing was used to minimize the effects of confounders, including indication bias. Associations of concomitant treatment with AZM and lung function outcomes were determined using linear mixed-effect models and generalized estimating equations. Cox proportional hazard regression models were used to evaluate associations with time to next PEx. Among the 10,660 people with CF included in the CFFPR-PHIS-linked dataset, 2,294 children and adolescents with 5,022 PExs that had intravenous tobramycin use were identified. A little less than half ( = 2,247; 45%) of all PExs were treated concomitantly with AZM and intravenous tobramycin. AZM use both at the most recent outpatient clinic encounter and during PEx treatment in combination with intravenous tobramycin was associated with a significantly lower absolute improvement in percentage-predicted forced expiratory volume in 1 second (ppFEV) (-0.93%; 95% confidence interval [CI], -1.78 to -0.07;  = 0.033), a lesser odds of returning to 90% or more of baseline ppFEV (odds ratio, 0.79; 95% CI, 0.68-0.93;  = 0.003), and a shorter time to next PEx requiring intravenous antibiotics (hazard ratio, 1.22; 95% CI, 1.14-1.31;  < 0.001) compared with intravenous tobramycin use without concomitant AZM. Concomitant AZM and intravenous tobramycin use for in-hospital PEx treatment was associated with poorer clinical outcomes than treatment with intravenous tobramycin without AZM. These results support the hypothesis that an antagonistic relationship between these two medications might exist.