Aim: The aim of this article is to evaluate the clinical and cost implications of failed endoscopic hemostasis in patients with gastroduodenal ulcer bleeding. Methods: A retrospective claims analysis of the Medicare Provider Analysis and Review (MedPAR) file was conducted to identify all hospitalizations for gastroduodenal ulcer bleeding in the year 2012. The main outcome measures were to compare all-cause mortality, total length of hospital stay (LOS), hospital costs and payment between patients managed with one upper gastrointestinal (UGI) endoscopy versus more than one UGI endoscopy or requiring interventional radiology-guided hemostasis (IRH) or surgery after failed endoscopic attempt. Results: The MedPAR claims data evaluated 13,501 hospitalizations, of which 12,242 (90.6%) reported one UGI endoscopy, 817 (6.05%) reported >1 UGI endoscopy, 303 (2.24%) reported IRH after failed endoscopy and 139 (1.03%) reported surgeries after failed endoscopy. All cause-mortality was significantly lower for patients who underwent only one UGI endoscopy (3%) compared to patients requiring >1 endoscopy (6%), IRH (9%) or surgery (14%), p1 endoscopy (eight days), IRH (nine days) or surgery (15 days), p1 endoscopy ($20,055), IRH ($34,730) or surgery ($47,589), p < 0.0001. Conclusions: Failure to achieve hemostasis at the index endoscopy has significant clinical and cost implications. When feasible, a repeat endoscopy must be attempted followed by IRH. Surgery should preferably be reserved as a last resort for patients who fail other treatment measures.