Objective To explore the changes of etiology and mortality of upper gastrointestinal bleeding (UGIB) in the last 20 years in Guangdong region. Methods A total of 3140 UGIB cases diagnosed in Guangdong General Hospital from January 1990 to October 2009 were analyzed with retrospective analysis. Groups were divided according to admission chronological order and age to analyze the causes of UGIB to get the trend of changes and influencing factors. Results UGIB occurred more in men than in women, the gender ratio was 2. 5∶1. There was no significant change in gender composition between the first and later 10 years. Peptic ulcer bleeding (PUB) was the main cause of UGIB in young and middle-age patients (age<60 years), especially duodenal ulcer (DU)bleeding (45. 0%) , and secondary was acute gastric mucosal lesion ( AGML) (16. 6%). While in elder patients group (age≥60 years), the main cause of UGIB was AGML (40. 5%), the frequency was significantly higher compared with the young and middle-age group (40. 5% vs 16. 6%,P<0. 01).Compared the first 10 years with the later 10 years, the occurrence rate of PUB was overall in downward trend (57. 4% vs 42. 8%, P<0.01), of which DU and compound ulcer(CU) bleeding reduced significantly (DU: 43.8% vs 27.7%, P<0. 01 and CU: 7.7% to 5.5%, P<0. 05). While the incidence of gastric ulcer (GU) (7.4% vs 8. 1% ,P>0. 05) and esophagogastric variceal bleeding (EVB) (11. 7% vs 12. 9%, P>0.05) remained stable. The occurrence of AGML bleeding significantly increased than before (32. 4% vs 18. 8%,P<0. 01), and became one of the most important causes of UGIB. Conclusions PUB is still the most important cause of UGIB in Guangdong region. AGML becomes another important cause of UGIB in elder patients, which may relate to the increasing use of non-steroidal anti-inflammatory drugs (NSAIDs), anti-platelet and antineoplastic medicine.