Background: Proton pump inhibitors (PPIs) are widely prescribed and may be associated with harm; hypomagnesemia and reduced effectiveness of calcium carbonate phosphate binders may be important in end-stage kidney disease (ESKD). Objectives: Our objectives included (1) discontinuing PPIs and H2 blockers and (2) assessing the impact on serum magnesium and markers of mineral metabolism. Design: Prospective cohort. Setting: Satellite hemodialysis unit of a tertiary care hospital. Patients: Incident and prevalent patients with ESKD treated with hemodialysis. Measurements: We assessed the impact of stopping PPI/H2 blockers in patients who did not have an absolute indication as per guidelines in the general population; serum magnesium, calcium, and phosphate were measured before and approximately 8 weeks later. Analysis of variance (ANOVA) test and Kruskal-Wallis was used to describe the population. Wilcoxon signed rank test for the paired change scores (from pre to post) Methods: The electronic medical record (EMR) was extensively searched for absolute indications for a PPI. Results were reviewed with the primary nephrology team before approaching patients about stopping the PPI. Basic demographic information and select medications were also collected. Results: Electronic medical records were reviewed for 179 patients, 74 had a PPI or H2 antagonist or both on their medication list (43%); 23 (31%) were assessed as appropriate. After primary team and patient review, 29 patients agreed to a trial of PPI withdrawal. Fourteen patients restarted their PPI, most for gastroesophageal reflux disease. Three patients had a GI bleed, 1 fatally. Serum calcium ( P = .17) and the dose of phosphate binders ( P = .075) did not change but serum phosphate increased (1.55 [0.29] to 1.85 [0.34] mmol/L; P = .0005). Serum magnesium also increased (1.01 [0.16] to 1.06 [0.14] mmol/L; P = .01). Limitations: Small patient numbers and observational nature of the study does not establish causation in this population at high risk to experience a gastrointestinal bleed. Conclusions: Our results suggest that PPI deprescribing as recommended in the general population may be associated with harm in patients with ESKD and requires further study. Trial Registration: Not registered.