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Rectal indomethacin or a topical spray of epinephrine to the papilla of Vater has each shown efficacy alone in the prevention of post–endoscopic retrograde cholangiopancreatography pancreatitis (PEP). We supposed that a submucosal epinephrine injection would be more effective and longer acting than a topical epinephrine spray and therefore would further reduce the incidence of PEP.A retrospective analysis was conducted of 412 patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 2017 and December 2019. These patients were divided into 2 groups: the indomethacin group and the indomethacin plus the submucosal epinephrine injection group. The incidence rates and severity of PEP, post-ERCP hyperamylasemia, other outcomes, and any other adverse events were compared between the groups.Baseline demographic and clinical characteristics and procedure-related parameters were similar between the 2 groups. The incidence of PEP was 0.4% in the epinephrine group compared with 5.1% in the indomethacin group (P<0.001). Post-ERCP hyperamylasemia occurred in 24.6% of patients in the indomethacin group, whereas 7.6% of patients in the epinephrine group developed this condition; the difference was significant (P<0.001). Postsphincterotomy bleeding occurred in 5 patients, all of whom were in the indomethacin group (P<0.001). Other adverse events, including arrhythmias, acute coronary events, stroke, or hypertension were not significantly different between the 2 groups.Addition of a submucosal epinephrine injection in conjunction with rectal indomethacin significantly reduced the incidence of PEP, post-ERCP hyperamylasemia, and postsphincterotomy bleeding.