First-line over-the-scope-clip (OTSC) treatment has shown higher efficacy than standard endoscopic therapy in acute non-variceal upper gastrointestinal bleeding (UGIB) from different causes. We performed a head-to-head randomized controlled trial (RCT) comparing OTSC vs through-the-scope-clip (TTSC) as first-line mechanical treatment in the specific setting of peptic ulcer (PU) bleeding. We conducted an international, multicenter RCT on consecutive patients with suspected UGIB. In case of Forrest Ia-IIb gastroduodenal PU, patients were randomized 1:1 to OTSC or TTSC treatment. The primary outcome was the rate of 30-day rebleeding after successful initial hemostasis. Secondary outcomes included successful initial hemostasis and overall clinical success rates, defined as the composite of successful initial hemostasis and no evidence of 30-day rebleeding. 251 patients were screened and 112 patients were finally randomized to OTSC (n=61) or TTSC (n=51) treatment. 30-day rebleeding rates were 1.6% (1/61) and 3.9% (2/51) for OTSC- and TTSC-treated patients, respectively (Kaplan-Meier log-rank, p = 0.458). Successful initial hemostasis rates were 98.4% (60/61) in the OTSC group and 78.4% (40/51) in the TTSC group (p=0.001). Eventually, overall clinical success rates were 96.7% (59/61) in the OTSC group and 74.5% (38/51) in the TTSC group (p=0.001). Low rates of 30-day rebleeding were observed after first-line endoscopic treatment of acute PU bleeding with either OTSC or TTSC. However, OTSC showed higher efficacy than TTSC in achieving successful initial hemostasis and overall clinical success.