Proton pump inhibitors (PPIs) are effective medications for acid-related disorders; however, they are also overused and may be associated with several adverse effects. A PPI stewardship program was implemented at one institution to combat the overuse of PPIs. The purpose of this study is to evaluate the effectiveness of an inpatient PPI stewardship program in reducing PPI use, both during hospitalization and upon discharge. This was a retrospective cohort study of all patients admitted to an internal medicine service at a single institution from March 14, 2016, to August 14, 2016, with an intervention by the PPI stewardship team. The primary objective was to determine the percentage of patients who tolerated inpatient and outpatient PPI discontinuation, or dose de-escalations upon discharge. Secondary objectives included the identification of risk factors for intolerance of PPI discontinuation, the occurrence of gastrointestinal (GI) complications after PPI discontinuation, and the percentage of patients who required "as needed" acid suppressive therapy (AST) with an antacid or histamine-2 receptor antagonist (H2RA) to control their symptoms while hospitalized. During the study time period, 537 patients with an active outpatient prescription for a PPI were admitted to an internal medicine team with 41.0% (n = 220) not meeting criteria for inpatient continuation. Of these patients, 95.9% (n = 211) tolerated inpatient PPI discontinuation, with 83.4% (n = 176) not requiring any "as needed" AST during hospitalization. Upon discharge, 57.1% patients (n = 24 of 42) tolerated PPI discontinuation at 3 months, while 81.8% patients (n = 18 of 22) tolerated PPI dose de-escalations at 3 months. Risk factors for intolerance of inpatient PPI discontinuation were a higher body mass index (BMI) (33.7 vs 30.3 kg/m, = .046) and longer length of stay (7.0 vs 4.0 days, = .03), while longer duration of PPI use (9.0 vs 5.5 years, = 0.03) was identified as a risk factor for intolerance of outpatient PPI discontinuation. One patient experienced reflux esophagitis 2 months after PPI discontinuation. A PPI stewardship program at a single institution resulted in the reduction of inappropriate PPI use in both the inpatient and outpatient settings.