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Introduction: There is a paucity of trials studying the role of intravenous (IV) proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) in the critically ill, and no trials comparing pantoprazole to famotidine, two commonly used agents for SUP. Methods: This is an ongoing prospective, open-label, randomized study of patients admitted to the ICU/CCU from January 2013 and onward. All patients are assessed for risk factors for stress-related mucosal bleeding (SRMB). Patients are randomized to famotidine 20 mg IV Q12H or pantoprazole 40 mg IV QAM. The primary endpoint is the incidence of overt and clinically significant upper gastrointestinal bleeding (CSUGB) until the patient is either transferred out of the ICU/CCU or expired. Secondary endpoints include length of stay (LOS), duration on mechanical ventilation, and drug-induced adverse drug events. Results: Patients were randomized to IV pantoprazole (n=68) and IV famotidine (n=61) with a median patient age of 72 years. Both groups had similar baseline characteristics including risk factors for SRMB (2.7 vs. 2.7, p=0.50), however the pantoprazole group had higher APACHE-II scores (23.9 vs. 20.1, p<0.01). The most common SRMB risk factors for pantoprazole and famotidine were mechanical ventilation (79.4% vs. 75.4%), acute renal failure (36.8% vs. 49.2%), coagulopathy (32.4% vs. 32.8%), and septic shock (33.8% vs. 27.9%). SRMB occurred in four patients in the pantoprazole group (3 overt bleeds, p=0.36 and 1 CSUGB, p=0.34) and one patient in the famotidine group (overt bleed). Patients given IV pantoprazole had similar mean ICU/CCU LOS (6.7 vs. 6.5 days, p=0.37) and duration on mechanical ventilation (6.5 vs. 6.3 days, p=0.39). Patients on pantoprazole (n=22) experienced more adverse effects than famotidine (n=10); hypomagnesemia (13 vs. 5) and nausea/vomiting (7 vs. 3); C. difficile diarrhea was the same in both groups (2 vs. 2). Conclusions: IV pantoprazole and IV famotidine are equally effective for SUP; however, more patients had UGB with pantoprazole indicating the plausible need for more frequent dosing. Pantoprazole was commonly associated with hypomagnesemia; questioning the prevailing belief that hypomagnesemia generally occurs only with chronic PPI use. The study is ongoing and will determine the efficacy and safety between both agents for SUP in the critical care setting.