Current guidelines vary as to their recommendations addressing the role of hemostatic powders when managing patients with malignant gastrointestinal (GI) bleeding as these are based on very-low to low quality evidence in large part due to a paucity of randomized trial data. This was a patient- and outcome assessor-blinded multicenter randomized controlled trial. Patients presenting with active bleeding from an upper or lower GI lesion suspected to be malignant at index endoscopy between June 2019 and January 2022 were randomly allocated to receive either TC-325 alone or standard endoscopic treatment (SET). The primary outcome was 30-day rebleeding, while secondary objectives included immediate hemostasis and other clinically relevant endpoints. Overall, 106 patients comprised the study population (55 TC-325 and 51 SET, after 1 exclusion in the TC-325 and 5 in the SET group). Baseline characteristics and endoscopic findings did not differ between groups. Thirty-day rebleeding was significantly lower in the TC-325 (2.1% TC-325 versus 21.3% SET,OR=0.09[0.01, 0.80],P=.003). Immediate hemostasis rates were 100% in the TC-325 versus 68.6% in the SET group (OR=1.45[0.93, 2.29],P < .001). Other secondary outcomes did not differ between the two groups. Independent predictors of 6-month survival included the Charlson comorbidity index (HR=1.17[1.05, 1.32], P =.007), and receiving an additional non endoscopic hemostatic or oncological treatment during 30 days after the index endoscopy (HR=0.16 [0.06, 0.43], P <.001) after adjustment for functional status, Glasgow-Blatchford score, and an upper GI source of bleeding. The TC-325 hemostatic powder results in greater immediate hemostasis rates followed by lower 30-day rebleeding rates when compared to contemporary SET. (ClinicalTrials.gov number,NCT03855904).