This retrospective study investigated the preventive effect of intravenous esomeprazole (IVEO) in the prevention of nonvarices upper gastrointestinal bleeding (NUGIB). This study enrolled 130 patients with NUGIB and all of them underwent successful endoscopic hemostasis, of which 65 cases received routine management and IVEO (Group A) and the other 65 cases received routine management alone (Group B). The primary outcome (recurrent bleeding rate within 72-hour, 7-day, and 30-day), and secondary outcomes ((all-cause mortality, bleeding-related mortality, blood transfused, hospital stay (day), and incidence of adverse events)) were compared between 2 groups. Patients in the group A showed lower recurrent bleeding rate within 72-hour( P < .05), 7-day ( P < .05), and 30-day ( P < .05), than that of patients in the group B. However, no significant differences were identified in all-cause mortality( P = .26), bleeding-related mortality ( P = .57), blood transfused ( P = .33), and hospital stay ( P = .74) between 2 groups. In addition, both groups had similar safety profile. This study found that routine management and IVEO was superior to the routine management alone for preventing the recurrent bleeding rate after successful endoscopic hemostasis in patients with NUGIB.