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Background: Gastrointestinal bleeding (GIB) is a common and potentially fatal condition with all-cause mortality ranging from 3 to 10%. Endoscopic therapy traditionally involves mechanical, thermal, and injection therapies. Recently, self-assembling peptide (SAP) has become increasingly available in the United States. When applied to an affected area, this gel forms an extracellular matrix-type structure allowing for hemostasis. This is the first systematic review and meta-analysis to assess the safety and efficacy of this modality in GIB. Methods: We performed a comprehensive literature search of major databases from inception to Nov 2022. The primary outcomes assessed were the success of hemostasis, rebleeding rates, and adverse events. The secondary outcomes assessed were successful hemostasis with monotherapy with SAP and combined therapy, which may include mechanical, injection, and thermal therapies. Pooled estimates were calculated using random-effects models with a 95% confidence interval (CI). Results: The analysis included 7 studies with 427 patients. 34% of the patients were on anticoagulation or antiplatelet agents. SAP application was technically successful in all patients. The calculated pooled rate of successful hemostasis was 93.1% (95% confidence interval (CI) 84.7–97.0, I2 = 73.6), and rebleeding rates were 8.9% (95% CI 5.3–14.4, I2 = 55.8). The pooled rates of hemostasis with SAP monotherapy and combined therapy were similar. No adverse events were noted related to SAP. Conclusion: SAP appears to be a safe and effective treatment modality for patients with GIB. This modality provides an added advantage of improved visualization over the novel spray-based modalities. Further, prospective, or randomized controlled trials are needed to validate our findings. [ABSTRACT FROM AUTHOR]