Purpose: Although endoscopic therapy is highly effective in control of acute gastrointestinal bleeding (GIB), a small portion of patients who fail to achieve hemostasis may require interventional radiologic procedures or surgery with increased morbidity. Cyanoacrylate compound is a tissue adhesive used as a hemostatic agent for treatment of gastric varices and intraoperative bleeding, but data on spray application in acute GIB is limited. The aim of this study is to evaluate the efficacy and safety of cyanoacrylate spray in patients with difficult to treat acute GIB. Methods: Consecutive patients from July 2010 to May 2012 hospitalized at Riverside County Regional Medical Center and Loma Linda University Medical Center who required cyanoacrylate compound spray for treatment of GIB were identified from an internal endoscopic database. Cyanoacrylate spray technique was used after failure of conventional endoscopic treatments per discretion of the endoscopist. Using a 23 gauge sclerotherapy needle positioned 1 cm outside the tip of the endoscope, 0.5-4.0 ml of commercially available cyanoacrylate compound (butyl-2-cyanoacrylate) was sprayed over the bleeding site followed by a rapid normal saline flush to prevent congealing. Results: During the study period, four patients required cyanoacrylate spray for difficult to treat acute GIB (Table). Patient 1 presented with hematochezia and hemodynamic instability requiring 16 units of PRBC. Upper endoscopy showed active arterial bleeding from a duodenal ulcer base, despite blind epinephrine injection. Half ml of cyanoacrylate spray achieved hemostasis. However, due to limited experience with this technique, the patient underwent IR embolization despite lack of rebleeding. Patient 2 with history of Osler-Webber-Rendu Syndrome presented with melena due to multiple gastric vascular ectasias. One ml of cyanoacrylate spray achieved hemostasis. The patient had rebleeding after 18 days possibly from a different gastric vascular ectasia. Patient 3 on aspirin presented with hematochezia and hemodynamic instability after polypectomy. Half ml of cyanoacrylate spray achieved hemostasis. Patient 4 presented with melena and hemodynamic instability from a duodenal ulcer with arterial spurting requiring 8 units of PRBC. Four ml of cyanoacrylate spray achieved hemostasis. Repeat EGD next day revealed no active bleeding. No immediate or delayed complications were noted on the four patients at a median follow-up of 42 days (range, 28-120).Table: [1773]Conclusion: In patients with active GIB that is difficult to control with conventional endoscopic modalities, cyanoacrylate spray achieved 100% hemostasis. This novel technique is simple, safe, and efficacious and should be considered in the armamentarium in the treatment of GIB.