Background & Aims: Endoscopic therapy reduces the rebleeding rate, the need for surgery, and the mortality in patients with peptic ulcer and active bleeding or visible vessel. Injection of epinephrine is the most popular therapeutic method. Guidelines disagree on the need for a second hemostatic procedure immediately after epinephrine; although it seems to reduce further bleeding, its effects on morbidity, surgery rates, and mortality remain unclear. The aim of this study was to perform a systematic review and meta-analysis to determine whether the addition of a second procedure improves hemostatic efficacy and/or patient outcomes after epinephrine injection. Methods: An extensive search for randomized trials comparing epinephrine alone vs. epinephrine plus a second method was performed in MEDLINE and EMBASE and in the abstracts of the AGA Congresses between 1990 and 2002. Selected articles were included in a meta-analysis. Results: Sixteen studies including 1673 patients met inclusion criteria. Adding a second procedure reduced the further bleeding rate from 18.4% to 10.6% (Peto odds ratio 0.53, 95% CI: 0.40 - 0.69) and emergency surgery from 11.3% to 7.6% (OR: 0.64, 95% CI: 0.46-0.90). Mortality fell from 5.1% to 2.6% (OR: 0.51, 95% CI: 0.31-0.84). Subanalysis showed that the risk of further bleeding decreased regardless of which second procedure was applied. In addition, the risk was reduced in all subgroups, although reduction was more evident in high-risk patients and when no scheduled follow-up endoscopies were performed. Conclusions: Additional endoscopic treatment after epinephrine injection reduces further bleeding, need for surgery, and mortality in patients with bleeding peptic ulcer.