Backgrounds/Aims: Acute pancreatitis is the most widespread complication of endoscopic retrograde cholangiopancreatography. Here, we investigated the efficacy of rectal suppository naproxen, sublingual isosorbide dinitrate and their co-administration in the prevention of post-ERCP pancreatitis. Methods: This double-blind randomized clinical trial carried out from June 2015 to February 2016 at the Gastrointestinal and Liver Diseases Research Center in Rasht, Iran. A total of 585 patients were selected from candidates for diagnostic or therapeutic ERCP by using the simple sampling method. Patients divided into three groups. Group A received 500 mg naproxen, group B took 5 mg isosorbide dinitrate, and group C was co-administrated both agents before ERCP. The primary outcome measure was the development of pancreatitis onset of pain in the upper abdomen and increase of serum amylase activity more than 3 times over the upper normal limit (60-100 IU/L) within first the 24 h post-ERCP. Results: Totally, 80 patients developed PEP included 29 (4.9%), 24 (4.1%), and 27 (4.6%) patients in groups A, B, and C, respectively (p=0.845). Longer ERCP time (p=0.041), using diazepam (p=0.033), a higher number of pancreatic ducts cannulation (p＜0.001), pancreatic duct injection (p=0.013), and using pancreatic stent (p=0.004) were the predisposing factors for PEP. Conclusions: Our findings indicated that prophylactic naproxen suppository or isosorbide dinitrate sublingually or co-administration had no significant difference in the prevention and severity of PEP, however, enhancing the endoscopist's skills can be effective. Departments and educational hospitals should develop their assessment and quality assurance measures for the training of fellows' not only technical training but also an understanding of the diagnostic and therapeutic roles of the procedure.