Background: Gastrointestinal hemorrhage (GIH) is the most common gastrointestinal endoscopic emergency. Some lesions are difficult to treat with traditional endoscopic hemostatic tools, for example, when significant endoscopic maneuvering is required, GIH is severe or diffuse, prior treatment(s) have failed, or malignancy associated hemorrhage is present. In such cases, a topical, endoscopically applied hemostatic powder (HS) is of interest due to simple "point and shoot" application. Aim: Primary outcome was immediate hemostasis of any GIH source. Secondary aims included rebleeding rate and transfusion requirement after HS. Methods: Patients undergoing endoscopy with HS application (Hemospray; Cook Medical, Bloomington, IN) for any indication at Mayo Clinic (Rochester, MN) from 2018-2019 were recorded in a prospectively maintained database. Results: 34 patients (76.5% male, mean age 60AE15.6y, mean ASA score 3.94AE0.74, mean Glasgow-Blatchford score 10.6AE3.5) underwent 34 procedures with single HS application. A significant minority were anticoagulated (35.3%; 17.6% warfarin, 8.8% unfractionated heparin, 5.9% bivalrudin, 2.9% rivaroxaban) and/or on antiplatelet therapy (14.7%; 5.9% high dose aspirin, 5.9% clopidogrel, 2.9% ticagrelor), while underlying bleeding diathesis was present in 73.5%, including 35.5% with cirrhosis, 8.8% end stage renal disease, 5.9% hematologic malignancy, and 29.4% other causes, such as presence of left ventricular assist device. Refer to Table 1 for endoscopic and lesion details during and for which HS was used. Briefly, HS was typically used inpatient (94.1%) to address upper GIH (55.9% stomach, 20.6% esophagus) more often than lower (8.8% right colon, 8.8% rectosigmoid). Most common GIH etiologies were: 29.4% postprocedure (i.e. polypectomy, endoscopic submucosal dissection, APC treatment), 20.6% malignancy, and 17.6% GAVE or portal hypertensive gastropathy. Providers intended for HS to be utilized as primary hemostasis in 21 (61.8%) cases. Immediate hemostasis was achieved in 32 (94.1%) cases. Refer to Figure 1 for rebleeding events attributed to the lesion for which HS was originally used up to 30 days following HS application. For inpatients, no difference was seen in the mean number of blood transfusion units prior to and after HS (5.8AE10.7 vs 5.3AE12.0). Overall, 15 (44.1%) patients died over a mean follow-up time of 111.8AE139.7 d; 3 (8.8%) deaths were attributed to GIH for which HS was used. No HS related adverse events were noted. Conclusion: HS is safe and effective across a variety of GIH sources. Users should expect immediate and durable hemostasis in the majority of patients, including when other therapies have failed. For patients failing long-term hemostasis, HS may be helpful in bridging patients to more definitive therapy.