Introduction: Endoscopes, particularly duodenoscopes, have been associated and implicated in the transmission of multi-drug resistant bacteria (MDRB). Our medical center has been voluntarily submitting cultures since 2012 to a reference laboratory surveying for the emergence of MDRB. We were informed in September 2013 that a cluster of patients treated at our institution had a unique AmpC-E. coli with a preponderance of those patients having had multiple ERCPs. Methods: Extensive chart reviews were undertaken to identify demographics, co-morbid conditions, procedures performed, and clinical outcomes. The entire endoscope reprocessing procedure was reviewed and investigated for quality assurance. All endoscopes were cultured post-reprocessing. Root-cause analysis and procedure modifications using mistake-proofing and successive checks were undertaken. Results: Thirty patients were identified of whom 17 had an underlying biliary obstruction secondary to carcinoma. The other 13 had benign biliary obstruction from complicated pancreatitis or stricturing biliary disease. All patients identified had undergone multiple ERCPs; the median number of ERCP’s was 2 (range 1 to 13) with all but one patient having had a stent. Eleven patients died during the study period, 7 with pancreatic cancer, 2 with PSC, 1 with pancreatic necrosis, and one after pancreas/kidney transplant. Root cause analysis demonstrated that scope reprocessing was at or exceeded manufacturers’ and professional societies’ recommendations and that the reprocessing room did not harbor MDRB. Despite this, post-reprocessing endoscope cultures continued to identify MDRB. The elevator and channel appeared to be the safe harbor for bacteria. Multiple resolutions were considered including gas sterilization with ethylene oxide, a process that was rejected due to doubts about efficacy. Ultimately, we implemented the “penalty box” solution in which reprocessed endoscopes were routinely cultured and not released for use until the cultures were confirmed negative for MDRB or other pathogenic organisms. Conclusion: Duodenoscopes are difficult to adequately reprocess under current manufacturers’ and professional societies’ recommendations. This can lead to the scopes serving as vectors of transmission for organisms, such as MDRB, into the GI tract. Once there, MDRB can lead to infection and/or colonization. Patients who have undergone multiple ERCPs seem to be at higher risk of MDRB infection, likely due to underlying comorbidities, high antibiotic exposure, and greater chance of inoculation of MDRB. These findings suggest a design flaw and/or inadequate reprocessing recommendations and have significant implications for high-volume ERCP centers.