Deprescribing is a recommended intervention to reduce morbidity and mortality caused by polypharmacy in older residents. However, a lack of definite deprescription guidelines and evidence of clinically meaningful outcomes complicates or precludes the practicality of such an approach. The objective of the present pilot study is to establish and implement a stepwise taper protocol that can potentially minimize overuse of proton pump inhibitors in a safe, effective, and feasible manner in the nursing home. Proton pump inhibitor dosage was reduced by half every 3 weeks until the lowest dose was reached; thereafter, the frequency was changed to every other day for 3 weeks, if tolerated. Subsequently, histamine receptor antagonists replaced proton pump inhibitors and followed the same deprescription regimen until discontinuation. Patient-specific interventions also included reassessment of therapeutic agents and dosage forms for more tolerable alternatives to facilitate deprescription efforts and minimize gastric ulceration or discomfort. The pilot study enrolled 10 patients (average age 65.6 years, medication burden 16.8 units, and antisecretory duration 37.5 months). Physicians accepted >95% of interventions, and 90% of patients achieved cessation at 12 weeks. Post cessation, none of the patients needed antacid, prokinetic, or antisecretory agents at 4 weeks. Difficulties in order interpretation and transcription among nurses as well as order entry and calculations among pharmacists were noted. The present pilot study added to the growing body of evidence that gradual deprescription of antisecretory medications is feasible. Nonetheless, the pilot design precludes any conclusions about safety and efficacy of the intervention.