Background: Stress ulcer prophylaxis (SUP) is a standard of care for intensive care unit (ICU) patients with known stress ulcer risk factors (SURFs). Proton pump inhibitors (PPIs) and histamine-2 receptor blockers (H2Bs) are the most common SUP medications. The higher potency of PPIs suggests more reduction in clinically important gastrointestinal bleeding (CIGIB) compared to H2Bs but higher risk of nosocomial pneumonia (NP) and clostridium-difficile associated diseases (CDAD). The goals of this study are to describe factors associated with SUP use and determine whether PPIs are associated with lower risk of CIGIB and higher risk of NP and CDAD compared to H2Bs in the ICU. Methods: Using Philips eICU Research Institute ICU database, a cohort of 572,519 adults admitted to 293 ICUs between 1/1/2008 and 6/30/2012 was created to study SUP use and outcomes. SUP use was defined as the administration PPIs, H2Bs, sucralfate or antacids during the ICU stay. Multivariable logistic regression was used to identify factors associated with use and with overuse; SUP overuse was defined as the receipt of SUP medications in patients without SURFs. Discrete-time Cox proportional hazard multivariable regression models were used to compare PPIs to H2Bs with regard to CIGIB, NP and CDAD. Results: The cohort comprised 76% Caucasians and 54% males; mean age was 62.4 years. SUP use was high (86.4%). While most of SURFs predicted SUP receipt, mechanical ventilation for more than 24 hours (odds ratio (OR) =10.6, 99% CI: 9.8-11.5) and organ transplantation (OR=13.3, 99% CI: 6.9-25.7) were the strongest predictors. PPIs were the most widely used (50 %) followed by H2Bs (18 %). Overuse of SUP medications was observed in 80% of ICU patients. Hazard of CIGIB was two times greater for PPI users compared to H2B users (adjusted hazard ratio (HR) 1.97 (95% CI: 1.48-2.63). Hazard of CDAD was not significantly different between the PPIs and H2B users (HR: 1.12, 95% CI: 0.89-1.41), while the risk of NP was lower among PPI compared to H2B users (HR: 0.87, 95%CI: 0.77-0.97). Conclusions: Knowledge generated from this study on factors associated with SUP use in the ICU, and comparative risks and benefits, can be used to identify and design interventions to improve guideline adherence and improve appropriateness of use and outcomes.