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Background: The use of acid suppressive agents became a standard therapy in an intensive care unit (ICU) to prevent stress related gastrointestinal mucosal damage. However, the risk of infectious diseases has been concerned. Objective: The study was to determine the differences between histamine 2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) in incidence of nosocomial pneumonia and pseudomembranous colitis (PMC) by Clostridium difficile with patients in ICU. Methods: This is a retrospective comparative study including patients admitted to the ICU who were at least 18 years of age and stayed for more than 48hrs from August 1, 2014 to January 31, 2015. The propensity score analysis and propensity matched multivariable logistic regression were used in analyzing data to control for confounders. Results: A total of 155 patients were assessed. H2RA were prescribed in 110 (53.9%) and PPI were in 45 (22.1%). Nosocomial pneumonia developed in 37 (23.9%); 25 (22.7%) were on H2RA and 12 (26.7%) were on PPI. The unadjusted incidence of nosocomial pneumonia was slightly higher in the patients with PPI (odds ratio (OR) 1.24; 95% confidence interval (CI): 0.54-2.71) compared to them with H2A. After adjusting with propensity score, the adjusted OR with PPI was 1.35 (95% CI: 0.44-4.11). The propensity score matched analyses showed similar results. Conclusion: The uses of PPI and H2RA as a stress ulcer prophylaxis agent showed similarity in the incidence of nosocomial pneumonia and PMC.