Introduction: Peptic ulcer disease (PUD) is the leading cause of upper GI bleeding. PUDs with an adherent clot (Forrest IIb) are associated with a high risk of rebleeding and mortality. However, the optimal management of bleeding PUD with adherent clots, including endoscopic or conservative therapy, remains unclear. The most recent ACG guidelines in 2021 did not clearly endorse endoscopic treatment for bleeding PUDs with adherent clot as opposed to medical therapy. We performed this systematic review and meta-analysis to compare the endoscopic and conservative therapeutic approaches to managing bleeding PUDs with adherent clot. Methods: We systematically searched MEDLINE, EMBASE, and the Web of Science databases through May 15, 2022, to include all randomized controlled trials (RCTs) comparing the endoscopic and conservative therapeutic approaches for bleeding PUDs with adherent clots. The outcomes of interest in our meta-analysis were rebleeding, need for surgery, and mortality. The random-effects model was used to calculate the weighted pooled risk ratio (RR) with the corresponding 95% confidence intervals (CI) of our desired outcome. A P-value , 0.05 was considered statistically significant. Heterogeneity was assessed using the Higgins I 2 index (I 2 values .50% implied the presence of significant heterogeneity). Results: Eleven RCTs with 839 patients (434 received endoscopic therapy vs. 405 received conservative therapy) were included. Endoscopic therapy group underwent clot removal and treatment of the underlying lesion with thermocoagulation, electrocoagulation, injection of sclerosants such as epinephrine or ethanol, or hemoclipping. Rebleeding occurred in 8.1% of patients in the endoscopic therapy group, compared to 20.7% in the conservative therapy group (RR 0.45, 95% CI 0.26-0.78, P50.004, I 2 534%, Figure A). We observed lower mortality of 3.7% in the endoscopic therapy group compared to 8% in the conservative therapy group (RR 0.49, 95% CI 0.25-0.96, P50.04, I 2 50%, Figure B). In addition, the need for surgery was significantly lower in the endoscopic therapy group (4.3%) compared to the conservative therapy group (9.9%) (RR 0.48, 95% CI 0.24-0.97, P50.04, I 2 50%, Figure C). Conclusion: Our meta-analysis demonstrated that endoscopic therapy is superior to conservative treatment for bleeding PUDs with an adherent clot regarding rebleeding, need for surgery, and mortality. However, large-scale RCTs are needed to validate our findings.