Background and Aims: Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography, and has remarkable rates of morbidity and mortality. The aim of this study is to investigate the effect of local epinephrine administration alone in reducing the frequency and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis. Materials and Methods: The data of 979 patients who underwent endoscopic retrograde cholangiopancreatography were evaluated retrospectively. Age, gender, indications for endoscopic retrograde cholangiopancreatography procedure, technique, conditions that increase the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis, presence of post-endoscopic retrograde cholangiopancreatography pancreatitis and it’s severity, serum amylase, leukocyte and C-reactive protein levels (before and after endoscopic retrograde cholangiopancreatography) were recorded. The data were compared between two groups as 473 patients who received only local epinephrine prophylaxis and 506 patients that did not. Results: Post-endoscopic retrograde cholangiopancreatography pancreatitis rate was 6.8% in all patients and 13.6% in patients with high risk. Post-endoscopic retrograde cholangiopancreatography pancreatitis was observed less frequently in the group that received local epinephrine prophylaxis when compared to the group that did not (9.1% vs 4.4%; p = 0.004). Post-endoscopic retrograde cholangiopancreatography amylase, leukocyte and C-reactive protein levels were significantly lower in the epinephrine group when compared to the null group (p = 0.001, p = 0.004, p = 0.001). Less severe and moderate pancreatitis was observed in the epinephrine group (p = 0.003). Local epinephrine irrigation was observed to reduce the rate of post-endoscopic retrograde cholangiopancreatography pancreatitis in patients with high risk (18.9% vs 7.9%; p = 0.002). Conclusion: Epinephrine irrigation with direct spraying method to major papillae is an easy-to-apply, safe and promising method in prevention of post- endoscopic retrograde cholangiopancreatography pancreatitis. Further studies with large populations are needed to investigate its effectiveness.