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Background EUS can provide access to the main pancreatic duct (MPD) for therapeutic intervention. The long-term clinical success of EUS-guided MPD interventions is unknown. Objective To determine technical and clinical success rates, predictors of success, and long-term outcomes of EUS-guided MPD intervention. Design Retrospective, single-center study. Setting Tertiary-care referral center. Patients Forty-five patients. Intervention EUS-guided MPD stent retrieval or placement. Main Outcome Measurements Technical and clinical success rates, adverse events, and long-term clinical outcomes. Results Among the 45 patients, 37 had undergone failed ERCP, and 29 had surgically altered anatomy. Median follow-up after initial EUS-guided intervention was 23 months. Two patients underwent EUS for stent removal, and EUS-guided MPD stent placement was attempted in 43 patients. Technical success was achieved in 32 of 43 patients (74%) with antegrade (n = 18) or retrograde (n = 14) stent insertion. Serious adverse events occurred in 3 patients (6%). Patients underwent a median of 2 (range 1-6) follow-up procedures for revision or removal of stents, without adverse events. Complete symptom resolution occurred in 24 of 29 patients (83%) while stents were in place, including all 6 with nondilated ducts. Stents were removed in 23 patients, who were then followed for an additional median of 32 months; 4 patients had recurrent symptoms. Among the 11 failed cases, most had persistent symptoms or required surgery. Limitations Retrospective study design, individualized patient management. Conclusion EUS-guided MPD intervention is feasible and safe, with long-term clinical success in the majority of patients. EUS provides important treatment options, particularly in patients who would otherwise undergo surgery.