The objective of this work was to assess the efficacy of continuous proton pump inhibitor (PPI) therapy in children and to evaluate changes in biochemical, endoscopic, and histologic parameters during such treatment. A retrospective review of children receiving PPI therapy continuously for 1 year or more with baseline and follow-up esophageal and gastric biopsies on treatment was conducted to assess type, frequency, and duration of PPI dosing, symptom relief, gastrin levels, histologic findings, and adverse events. A total of 113 children (59 male, median age 4.5 years) were identified. Of these, 31% (35/113) were neurologically impaired. The median treatment duration was 35.2 months. Elevated serum gastrin levels occurred in 73% of children with no statistically significant differences in gastrin level by PPI type, dose, and dosing frequency or treatment duration. Adverse events were reported by 12% of children: diarrhea (5%) and constipation (4%) were the most frequent. Long-term PPI therapy appears to be effective, safe and well tolerated in children despite some biochemical, endoscopic, and histologic changes.