As the most common complication of endoscopic retrograde cholangiopancreatography (ERCP) is acute pancreatitis, researchers have paid due attention to minimize this complication using various drugs, one of which is epinephrine. Therefore, the present study aimed at evaluating the effectiveness of epinephrine spray on the papilla in preventing post-ERCP pancreatitis (PEP). The present double-blind clinical trial was performed on 164 patients undergoing ERCP. Patients in both groups received 50 mg rectal suppository as usual before ERCP. Then, during ERCP, epinephrine or normal saline was sprayed topically on the major papillae. After the intervention, patients were evaluated in terms of the incidence of PEP. The results of the present study revealed that the incidence of PEP in the epinephrine and control groups was 2.4% and 4.9%, respectively (P > 0.05). There was no significant difference between the two groups in terms of the incidence of bleeding after ERCP, number of accidental pancreatic duct cannulation, the increase in vision during common bile duct cannulations, the need for precut sphincterotomy, and the number of hospitalization days (P > 0.05). In addition, the chance of developing PEP was lower and higher in patients with higher ages (odds ratio [OR]: 0.86; P = 0.030) and biliary sludge (OR: 4.97; P = 0.042), respectively. As compared with indomethacin alone (control group), it seems that the administration of epinephrine can be effective in reducing the incidence of PEP, although this relationship was not recognized to be significant in this study and only the age and the presence of sludge had a negative and positive relationship with the incidence of PEP, respectively.