Objective: Acid suppression with histamine-2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) is recommended for children with persistent gastroesophageal reflux disease symptoms. In this retrospective, observational postauthorization study, we aimed to assess and compare safety outcomes in pediatric first-time users of esomeprazole, other PPIs or H2RAs. Methods: Data on children (aged 0–18 years) first dispensed esomeprazole, other PPIs or H2RAs between September 2008 and August 2011 was obtained from the Dutch PHARMO Database Network. Hospitalizations for seven predefined safety outcomes were evaluated (maximum follow-up: 18 months). Rate ratios were calculated using Poisson regression adjusted for baseline imbalances. Discharge letters were reviewed for event occurrence confirmation. Results: Of 23,470 included children, 2820 (median age: 3 years) were prescribed esomeprazole, 13,818 (median age: 15 years) other PPIs and 6832 (median age: 5 years) H2RAs. In total, 504 (2%) children were hospitalized for 762 predefined events: gastroenteritis (246); convulsion/seizure (200); pneumonia (154); failure to thrive (119); acute interstitial nephritis (19); thrombocytopenia (23); and angioneurotic edema (1). Significant differences between cohorts were observed only for failure to thrive, with adjusted rate ratios (95% confidence interval) for esomeprazole of 6.1 (2.4–15.7) vs. other PPIs and 6.1 (2.9–12.8) vs. H2RAs among current users. Occurrence was confirmed for 74% of assessable events. Confirmation rates were highest for pneumonia (81%) and lowest for failure to thrive (40%). Conclusions: Hospitalization rates for predefined outcomes were low and mostly similar in pediatric first-time users of PPIs and of H2RAs. Trial registration: NCT01338363.