Background A limited number of trials have investigated the efficacy of proton pump inhibitors for peptic ulcer bleeding, and some study design issues have been identified. Aim To present the design of a large trial evaluating the effects of intravenous esomeprazole on clinical outcomes in high-risk patients who have undergone endoscopic haemostasis for peptic ulcer bleeding. Methods The Peptic Ulcer Bleed study is an international, randomized, double-blind, placebo-controlled trial comparing either esomeprazole 80 mg intravenous bolus infusion for 30 min followed by esomeprazole 8 mg/h intravenously for 71.5 h, or placebo infusion for 72 h, after successful endoscopic haemostasis in patients with peptic ulcer bleeding and associated high-risk stigmata. All patients will receive once daily oral esomeprazole 40 mg for 27 days after intravenous therapy. The primary end point is the rate of clinically significant re-bleeding during the first 72 h after endoscopy. Secondary end points include: rate of re-bleeding during the first 7 and 30 days after treatment; length of hospitalization; mortality; blood transfusion; endoscopic re-treatment and surgery. Results Expected 2008. Conclusions The carefully designed protocol and quality control measures represent a pragmatic approach to contemporary challenges in peptic ulcer bleeding management and, it is hoped, qualify the Peptic Ulcer Bleed study as a new standard for future interventional studies.