Background: Endoscopic retrograde cholangiopancreatography (ERCP) is one of the main therapeutic and sometimes diagnostic methods in biliary and pancreatic diseases. A grading system for the difficulty of ERCP (grade one to four, the higher grade represents the more complexity of the procedure) has been developed by the American Society for Gastrointestinal Endoscopy (ASGE). This study aimed to assess the prevalence of ERCP-related complications, their common risk factors, and specifically the role of difficulty of the procedure based on ASGE grading. Material and Methods: This cross-sectional study was performed on 620 ERCP-operated patients over 4 years in two tertiary referral centers affiliated with Isfahan University of Medical Sciences. Data about the difficulty of procedures based on the ASGE grading scale, complications including pancreatitis, bleeding, infection, perforation, arrhythmia, respiratory suppression, aspiration, and major common risk factors were collected. Results: The overall prevalence of complications was 11.6% including pancreatitis 8.2%, perforation 0.8%, gastrointestinal bleeding 1.3%, cholangitis 2.4%, and cardiopulmonary problems 0.5% (arrhythmia 0.3% and respiratory depression 0.2%). Patients with pancreatic contrast injection (66.7% vs. 11.3% P = 0.04) and sphincter of Oddi dysfunction (SOD) (44.4% vs. 11.1%; P = 0.01) showed a statistically significant higher overall complication rate. The association of these risk factors remained significant in multivariable logistic regression analysis. Patients with pancreatic contrast injection also showed a statistically significant higher prevalence of post-ERCP pancreatitis (66.7% vs. 11.3% P = 0.04). Furthermore, a significantly higher prevalence of arrhythmia (3.6% vs. 0; P = 0.008) was observed among patients with difficult cannulation. Based on the ASGE difficulty grading score, most of the patients were classified as grade 2 (74.2%) and 3 and 4 (23.4%). No statistically significant difference was noted between the difficulty-based groups in terms of complications. Conclusion: The current study showed that the most critical risk factors of ERCP-induced complications were pancreatic contrast injection and SOD. ASGE grading scale for ERCP complexity did not predict the occurrence of complications in our study population.