BACKGROUND & AIMS: Alcohol use and cigarette smoking are associated with various pancreatic diseases, but it is not known whether they associate with post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). We performed a retrospective case-control study to determine if these activities increase the risk of PEP. METHODS: We identified 7638 patients who had undergone ERCP in the University of Michigan Health System and applied exclusion criteria to identify 123 with PEP. We randomly selected 308 age- and sex-stratified controls (2.5-fold case sample); after applying exclusion criteria 248 remained. In a masked fashion, we collected data for alcohol use, cigarette smoking, and 5 internal control variables: suspected sphincter of Oddi dysfunction (SOD), pancreatic sphincterotomy, moderate/difficult cannulation, 2 or more pancreatic injections, and pancreatic stent placement. RESULTS: The univariate model showed an increased frequency of PEP in current drinkers (P < .001), former drinkers (P < .001), and former smokers (P < .001), as well as patients who were suspected of having SOD (P < .001), had undergone pancreatic sphincterotomy (P < .001), had a moderate/difficult cannulation (P = .001), and/or had 2 or more pancreatic injections (P = .007). The frequency of PEP was reduced in current smokers (P < .001). The multivariate model showed that the only independent significant predictors of PEP were current drinking (odds ratio [OR], 4.70; 95% confidence interval [CI], 2.60-8.50; P < .0001), former cigarette smoking (OR, 3.29; 95% CI, 1.28-8.44; P < .013), suspected SOD (OR, 3.69; 95% CI, 1.94-7.02; P < .001), and pancreatic sphincterotomy (OR, 5.91; 95% CI, 2.04-17.14; P = .001). CONCLUSIONS: Current alcohol use and potentially former cigarette smoking are new risk factors for PEP. It is important to consider these variables in designing PEP prevention trials.