Background: Critically ill patients may develop visible gastric mucosal injury and stress ulcer soon after admission to an intensive care unit causing upper gastrointestinal bleeding as an important complication. Histamine-2 receptor antagonist (H2RA) prophylactic therapy has been documented to significantly decrease the incidence of upper GI bleeding in critically ill patients. This study was carried out in order to compare the effects of intravenous doses of ranitidine and enteral form of omeprazole suspension on preventing GI bleeding among ICU patients. Materials and Methods: This study was a double-blind randomized clinical trial conducted on patients admitted to the ICU at the Imam Hossein Hospital in Tehran, Iran. The patients were randomly divided into two groups of A and B. In group A, ranitidine was used as the prophylactic drug against GI bleeding with the dosage of 50 mg two times a day accompanied by placebo gavages through nasogastric tube. In group B, 20 mg of a suspension of omeprazole two times a day was gavaged in addition to 2cc of a parenteral placebo drug. Of 198 patients admitted to the ICU, 69 patients did not meet the inclusion criteria and a total of 129 patients enrolled in this study. Results: During the study 14(20.58%) cases in the ranitidine group and 3(4.9%) in the omeprazole group developed significant GI bleeding. Incidence of GI bleeding showed a significant difference between the two groups using the chi-square test. Of the 68 patients receiving ranitidine, 44 (67.7%) died. This rate was 38 in those receiving omeprazole (62%). Of the patients given ranitidine who faced overt GI bleeding, 12 (85.7%) died. This rate was 3 in the omeprazole group (100%). Conclusion: This study showed a statistically significant difference between omeprazole and ranitidine in preventing overt GI bleeding among ICU patients; but it failed to indicate any difference in prophylaxis of clinically important GI bleeding between the two drugs. (Tanaffos 2009; 8(4): 37-42)