IMPORTANCE: Proton pump inhibitors (PPI) are commonly prescribed to children with oropharyngeal dysphagia and resultant aspiration based on the assumption that these patients are at greater risk for reflux-related lung disease. There is little data to support this approach and the potential risk for increased infections in children treated with PPI may outweigh any potential benefit. OBJECTIVE: The aim of this study was to determine if there is an association between hospitalization risk in pediatric patients with oropharyngeal dysphagia and treatment with PPI. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study to compare the frequency and length of hospitalizations for children who had abnormal results on videofluoroscopic swallow studies that were performed between January 1, 2015, and December 31, 2015, and who were or were not treated with PPI, with follow-up through December 31, 2016. Records were reviewed for children who presented for care at Boston Children’s Hospital, a tertiary referral center. Participants included 293 children 2 years and younger with evidence of aspiration or penetration on videofluoroscopic swallow study. EXPOSURES: Groups were compared based on their exposure to PPI treatment. MAIN OUTCOMES AND MEASURES: The primary outcomes were hospital admission rate and hospital admission nights and these were measured as incident rates. Multivariable analyses were performed to determine predictors of hospitalization risk after adjusting for comorbidities. Kaplan-Meier curves were created to determine the association of PPI prescribing with time until first hospitalization. RESULTS: A total of 293 patients with a mean (SD) age of 8.8 (0.4) months and a mean (SD) follow-up time of 18.15 (0.20) months were included in the analysis. Patients treated with PPI had higher admission rates (Incidence rate ratio [IRR], 1.77; 95% CI, 1.16-2.68) and admission nights (IRR, 2.51; 95% CI, 1.36-4.62) even after adjustment for comorbidities. Patients with enteral tubes who were prescribed PPIs were at the highest risk for admission (hazard ratio [HR], 2.31; 95% CI, 1.24-4.31). CONCLUSIONS AND RELEVANCE: Children with aspiration who are treated with PPI have increased risk of hospitalization compared with untreated patients. These results support growing concern about the risks of PPI use in children.