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Background: Appropriate prescription of Proton pump inhibitors (PPIs) remains an important concern amid the rising overuse. A gap exists in the literature regarding the benefit of PPI prophylaxis and the consequences of underprescription in patients at risk for upper gastrointestinal bleeding (UGIB)., Aims: This study aims to describe the characteristics of hemorrhage in relation to PPI use in patients experiencing UGIB, with a focus on high-risk individuals requiring gastroprotection., Methods: Data from a French multicentric cohort of patients experiencing UGIB were analyzed. Patients using PPI were compared to those without PPI considering bleeding etiologies and outcomes of peptic ulcer disease (PUD)-related hemorrhage. The rate of PPI use and its effect on bleeding characteristics in high-risk populations, defined based on international guidelines, were also assessed., Results: Among 2497 included patients, 31.1% were on PPI at bleeding onset. PPI users exhibited a significantly lower rate of PUD-related bleeding in comparison with those without PPI (24.7 vs 40.8%, respectively, p < 0.0001). Similar difference was observed in high-risk populations, of whom, only 40.3% had gastroprotection with PPI before bleeding onset. PPI prophylaxis, however, did not influence the severity of bleeding in the general study population or in high-risk groups. Multivariate analysis identified age, comorbidities, and having more than two anti-thrombotic agents as predictors of severe bleeding., Conclusions: PPI users appear to have a lower rate of bleeding ulcers compared to non-users. However, underprescription in high-risk groups raises the need for standardized care to ensure appropriate PPI use., Competing Interests: Declarations Conflict of interest Authors have no relevant financial or non-financial competing interests to disclose concerning this work., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)