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Introduction: Critically ill patients may develop bleeding caused by stress ulceration (SU). Stress ulcer prophylaxis (SUP) is commonly used in the intensive care unit (ICU) to prevent SU but may be associated with complications including Clostridium difficile (CD) infection and nosocomial pneumonia (NP). Methods: A retrospective database analysis of ICU patients admitted to a 54 bed medical-surgical ICU between 07/2009 and 02/2013 was performed. Patients were identified based on the indications for SUP (duodenal ulcer, gastric ulcer, H. Pylori infection, erosive esophagitis, mechanical ventilation, coagulopathy, and gastroesophegeal reflux disease). Outcomes included development of GI bleed (GIB), CD infection, and NP up to 30 days. Either histamine receptor antagonists or proton pump inhibitors were prescribed for SUP. Results: The database contained 14,280 patients, out of which 12825 (89.8%) received SUP (SUP group) and 1455 (10.2%) did not (NSUP group). In the SUP group, 4360 (34%) had an indication for SUP, vs 37 (2.4%) of the patients in the NSUP group had an indication for SUP. GIB developed in 353 (2.8%) patients in the SUP group vs 6 (0.4%) patients in the NSUP group (Odds ratio [OR]= 7.0; 95% confidence interval [95% CI], 3.1 – 15.7, p < 0.0001). CD developed in 230 (1.8%) patients in the SUP group vs 14 (0.9%) patients in the NSUP group (OR= 1.9; 95% CI, 1.1 – 3.2, p = 0.02). NP developed in 71(0.6%) patients in the SUP group vs 2 (0.1%) patients in the NSUP group (OR= 4.0; 95% CI, 1.0 – 16.5, p = 0.05). Conclusions: Stress ulcer prophylaxis was prescribed for more patients than indicated and was associated with an increased incidence of Clostridium difficile infection and nosocomial pneumonia. The administration of SUP should be guided by established indications and undergo continuous quality assessment to prevent overutilization.