Background/Aim:The prevalence of acute upper gastrointestinal bleeding (AUGIB) has undergone a change after implementation of eradication therapy for Helicobacter pylori in peptic ulcers effective prevention of esophageal variceal bleeding and eventually, progressive use of low dose aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). To evaluate this subject, we performed a prospective study in two main University Hospitals of Shiraz (the largest city of southern Iran).Materials and Methods:All adults who were admitted in emergency room with impression of AUGIB and existing patients who developed AUGIB were included in the study. Gastroscopy was done with a follow-up for the next 15 days.Results:572 patients (mean age: 54.9 years) entered in the study. The most common presenting symptom was hematemesis or coffee-ground vomits (68%). 75% of patients gave history of consumption of low dose aspirin or other NSAIDs regularly. Gastric and/or duodenal ulcers were the most common causes (252/572, 44%) of AUGIB (Gastric ulcer: 173/572, 30% and duodenal ulcer: 93/572, 16%, respectively). Esophageal varices were the third common cause (64/572, 11%). 36 (6%) of the patients died. Mean age of these patients was higher than the patients who were alive (64.8 vs. 54.2 years, P = 0.001). Other than age, orthostatic hypotension on arrival (267/536 vs. 24/36, P = 0.018) and consumption of steroids (43/536 vs. 10/36, P = 0.001) were significant factors for increasing mortality.Conclusions:The most common cause of AUGIB, secondary only to NSAIDs consumption, is gastric ulcer. Mortality of older patients, patients who consumed NSAIDs and steroids concomitantly, and patients with hemodynamic instability on arrival were higher.