Background: Patients with Roux-en-Y gastric bypass (RYGB) anatomy pose challenges when endoscopic retrograde cholangiopancreatography (ERCP) is required. Deep enteroscopy-assisted ERCP can allow pancreaticobiliary intervention in these patients, but with limited success. This case series describes endoscopic ultrasound-directed transgastric ERCP (EDGE) for patients following RYGB. Methods: Patients with RYGB anatomy undergoing EDGE at a tertiary care center were included in this prospective single-arm feasibility study. All procedures were performed in two stages. First a 16-Fr percutaneous endoscopic gastrostomy (PEG) was placed in the excluded stomach using endoscopic ultrasound (EUS) guidance. Second, ERCP was performed through the newly fashioned gastrostomy and a transcutaneous fully covered metal esophageal stent. Results: Six patients (5 women, 1 man) with RYGB anatomy underwent EDGE. EUS-guided PEG placement was successful in all six patients (100%). Antegrade ERCP was successful in all six patients (100%) with the stages being separated by a mean of 5.8 days. The mean procedure times for the two stages were 81 minutes and 98 minutes. Two patients (33%) had localized PEG site infections that were managed with oral antibiotics. There were no adverse events related to ERCP. Conclusions: EDGE is both feasible and safe to perform in RYGB patients. Given the high success rates of our recent experience, we suspect that this technique can be performed as a one-stage procedure to provide a cost-effective, minimally invasive option for a common problem in a growing patient population.