Background: Anti-acids drugs are commonly used for stress ulcer prophylaxis (SUP). Some inpatients receiving acid suppression therapy without risk factors for nosocomial upper gastrointestinal bleeding and this inappropriate usage increase time, costs and avoidable side effects such as hospital-acquired pneumonia. Purpose: This study was designed to evaluate the prevalence of stress ulcer prophylactic drugs use, the number of properly indicated administrations and prescription prevalence of intravenous use of proton pump inhibitors (PIPs) and H2-antagonists in preventing nosocomial gastrointestinal bleeding and pneumonia. Methods: This cross-sectional study was performed on 280 patients in two different time zone before and after implementing of guidelines for SUP usage on the medical service in January and March of 2014(pre-intervention period) and January and march of 2015 (post-intervention period). Indicated anti-acid therapy for stress ulcer prophylaxis was defined according to the 1999 American Society of Health-System Pharmacists (ASHP) guidelines for the use of SUP. The Patient’s data such as kind of stress ulcer prophylaxis drug, ICU admission and the indication of prophylaxis pre and post-intervention were collected. Data were analyzed by SPSS software using the Pearson Chi-square test and unpaired t-test. Results: There was no significant change in the administration of stress ulcer prophylaxis drugs in general, but anti-acid medications misused decreased from 63.6% to 55.2% after intervention. Conclusion: The use of anti-acids without proper indication had 11.4% fall. The IV administration had a dramatic decrease as opposed to PO anti-acids use, which had a significant effect on hospital financial costs. In the end, there was no significant change detected in the total use of SUP (stress ulcer prophylaxis).