The risk of occurrence of gastrointestinal bleeding occurs in patients who have critical conditions in the Intensive Care Unit (ICU) so that the need for the use of stress-ulcer prophylactic agents is very appropriate to reduce the incidence of bleeding in the ICU. Stress-ulcer prophylactic agents that are often used in Indonesia are PPI (Proton pump inhibitors) such as Omeprazol, Lansoprazol, Pantoprazole and Esomeprazol. This research aims to determine the effectiveness of the use of the stress prophylactic agents ulcer the drug omeprazol and esomeprazol drugs in the ICU RS Bethesda Yogyakarta. The study used observational methods using retrospective cohort studies. The subject of research is all patients who are treated in ICU at Bethesda Yogyakarta Hospital during the period of January 2016-July 2018 which meets the criteria of inclusion and exclusion. This study was conducted to see the effectiveness of the drug omeprazol and esomeprazol by seeing the absence of major bleeding or minor bleeding in the patient's medical record data. The subject in this study amounted to 62 patients, with each group of omeprazol therapy 30 patients and esomeprazol 32 patients. Comparison of the number of patients who did not suffer from gastrointestinal bleeding between the group of omeprazol with the group esomeprazol is 30% and 21.9% with value (P = 0,465). There is no significant difference in effectiveness of the use of ulcer stress prophylactic therapy between omeprazol Group and esomeprazol Group.