Background: Topical hemostatic agents emerged as a new treatment modality for gastrointestinal bleeding. The aim of the study is to assess the safety and efficacy of PuraStat for control of active bleeding and for prevention of bleeding after different operative endoscopy procedures. Methods: A national, multicenter, observational registry was established to collect data from ten Italian centers from June 2021 to February 2023. Demographics, type of application (active gastrointestinal bleeding or prevention after endoscopic procedures, site, amount of gel used, completeness of coverage of the treated area), outcomes (rates of intraprocedural hemostasis and bleeding events during a 30-day follow-up) and adverse events were prospectively analyzed. Results: 401 patients were treated for an active gastrointestinal bleeding or as a preventive measure after different types of operative endoscopy procedures. 91 treatments for active bleeding and 310 preventive applications were included. In 174/401 (43.4%) PuraStat was the primary treatment modality. A complete coverage was possible in 330/401 (82.3%) with difficulty in the application in 7/401 (1.7%) of cases. Hemostasis of active bleedings was achieved in 90/91 patients (98.9%). In the 30-day follow-up 3.9% patients in whom PuraStat was used for prophylaxis had a bleeding event as compared with 7.7% after hemostasis. No adverse events related to the use of PuraStat were reported. Conclusions: PuraStat is a safe and effective hemostat both for bleeding control and for bleeding prevention after different operative endoscopy procedures. Our results suggest that the possible applications for the use of PuraStat may be wider compared to current indications.