Background: We sought to identify high-risk areas of pancreatic cancer incidence, and determine if clusters of persons diagnosed with pancreatic cancer were more likely to be located near arsenic-contaminated drinking water wells. Methods: A total of 5,707 arsenic samples were collected from December 2000 to May 2008 by the Florida Department of Health, representing more than 5,000 individual privately owned wells. During that period, 0.010 ppm (10 ppb) or greater arsenic levels in private well water were considered as the threshold based on standard of United States Environmental Protection Agency (EPA). Spatial modeling was applied to pancreatic cancer cases diagnosed between 1998–2002 in Florida (n = 11,405). Multivariable logistic regression was used to determine if sociodemographic indicators, smoking history, and proximity to arsenic-contaminated well sites were associated with residence at the time of pancreatic cancer diagnosis occurring within versus outside a cluster. Results: Spatial modeling identified 16 clusters in which 22.6% of all pancreatic cancer cases were located. Cases living within 1 mile of known arsenic-contaminated wells were significantly more likely to be diagnosed within a cluster of pancreatic cancers relative to cases living more than 3 miles from known sites (odds ratio = 2.1 [95% CI = 1.9, 2.4]). Conclusions: Exposure to arsenic-contaminated drinking water wells may be associated with an increased risk of pancreatic cancer. However, case–control studies are needed in order to confirm the findings of this ecological analysis. These cluster areas may be appropriate to evaluate pancreatic cancer risk factors, and to perform targeted screening and prevention studies.