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Despite advances in endoscopic and pharmacological treatment for peptic ulcer bleeding (PUB), mortality remains at 5–10% worldwide. Our aim was to investigate the causes of death in a prospective cohort of PUB in a tertiary referral center.Between 1993 and 2005, all patients with upper gastrointestinal bleeding (UGIB) admitted to the Prince of Wales Hospital were prospectively registered. Demographic data, characteristics of ulcer, and pharmacological, endoscopic, and surgical therapy, were documented. Mortality cases were classified as (A) bleeding-related death (A1: uncontrolled bleeding, A2: within 48 h after endoscopy, A3: during surgery for uncontrolled bleeding, A4: surgical complications or within 1 month after surgery, and A5: endoscopic related mortality) or (B) non-bleeding-related death (B1: cardiac causes, B2: pulmonary causes, B3: cerebrovascular disease, B4: multiorgan failure, and B5: terminal malignancy).In all, 18,508 cases of UGIB were enrolled; among them, 10,428 cases from 9,375 patients were confirmed to have PUB, and 577 (6.2%) patients died. There were significantly more patients who died of non-ulcer bleeding causes (79.7%) than bleeding causes (18.4%). The mean (s.d.) age of those who died of bleeding-related causes was higher (75.4 (12.6) years) than that of those who died of non-bleeding causes (71.7 (13.1) years) (P=0.010). Most bleeding-related deaths occurred when immediate control of bleeding failed (29.2%) or when patients died within 48 h after endoscopic therapy (25.5%). Among those who died of non-bleeding-related causes, multiorgan failure (23.9%), pulmonary conditions (23.5%), and terminal malignancy (33.7%) were most common.The majority of PUB patients died of non-bleeding-related causes. Optimization of management should aim at reducing the risk of multiorgan failure and cardiopulmonary death instead of focusing merely on successful hemostasis.