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Background. Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains common, and severe complications are associated with ERCP. There is no previous study detailing the effect of race and gender in a US-based population on risk of PEP. Methods. Data were collected on 269 “first-performed” consecutive ERCPs followed by division by race (White vs. African-American) and sex (Female vs. Male). A total of 53 probable risk factors were evaluated by uni- and multivariate analysis followed by outcomes expressed as an odds ratio (OR) (with a 95% confidence interval, 95% CI). Finally, a principal component analysis was performed to construct a risk prediction model for PEP, which can be used by clinicians at bedside. Results. After analyzing the risk factors based on race and gender-based groups, Caucasian males with PEP are more likely to have prior history of pancreatitis (<i>p</i> = 0.009), lower hemoglobin (<i>p</i> = 0.02)/blood urea nitrogen (BUN) (<i>p</i> = 0.01)/creatinine before ERCP (<i>p</i> = 0.07) and lower BUN (<i>p</i> = 0.01)/creatinine after ERCP (<i>p</i> = 0.07), while Caucasian females with PEP are more likely to have higher white blood cell (WBC) count before ERCP (<i>p</i> = 0.08) and lower amylase (<i>p</i> = 0.10)/bilirubin (<i>p</i> = 0.09)/aspartate aminotransferase (AST) after ERCP (<i>p</i> = 0.08). African-American males with PEP are more likely to have lower weight (<i>p</i> = 0.001)/smaller height (<i>p</i> = 0.0005)/lower alkaline phosphatase (<i>p</i> = 0.002)/AST (<i>p</i> = 0.04)/alanine transaminase (ALT) (<i>p</i> = 0.03) before ERCP and lower alkaline phosphatase (<i>p</i> = 0.002)/AST (<i>p</i> = 0.01)/ALT (<i>p</i> = 0.004) after ERCP, while African-American females with PEP are more likely to have prior history of pancreatitis (<i>p</i> = 0.004)/higher lipase before (<i>p</i> = 0.0001) and after (<i>p</i> = 0.05) ERCP along with increased risk with pancreatic duct cannulation (<i>p</i> = 0.0001) and injection (<i>p</i> = 0.0001)/biliary sphincterotomy (<i>p</i> = 0.0001). Importantly, prior history of ERCP, elevated AST after ERCP, and BUN prior to ERCP were found to be important clinical features predicting post-ERCP pancreatitis. To our knowledge, this is a first known attempt at developing a risk scoring system for PEP in a US population with decision tree learning. Conclusions. It is very evident that both patient and procedure-related risk factors vary by race and gender in the US population, leading to the development of a new risk assessment tool for PEP that can be used in clinical practice. We need to follow up with a larger prospective study to validate this novel race and gender-based risk scoring system for PEP.