INTRODUCTION: Approximately 100 cases of pyeloduodenal fistula (PDF) have been reported in the literature. PDF most often results from pyelonephritis due to nephrolithiasis, when inflammation extends to the duodenum given its relative immobility and lack of posterior peritoneal covering. Diagnosis of a PDF is usually made with computed tomography (CT) of the abdomen with contrast. The mainstay of therapy for PDF is nephrectomy and primary closure of the duodenum. We are presenting the second documented case of endoscopic closure of a PDF using the over-the-scope clip (OTSC) system and the third case of endoscopically treated PDF. This method provides an alternative to open surgery. CASE DESCRIPTION/METHODS: A 62 year old female presented with sharp, severe abdominal pain. She denied back pain, hematuria, fever, and dysuria. She had no significant past medical history and did not take any medications. CT abdomen and pelvis demonstrated a large right-sided staghorn calculus extending into the renal pelvis. The patient underwent percutaneous nephrolithotomy, which was complicated by perforation of the renal pelvis and abdominal compartment syndrome. Subsequently, a proximal ureteral stricture was refractory to stenting and balloon dilation. CT urography demonstrated a PDF (Image 1). After placement of a metallic ureteral stent and nephrostomy tube, a nephrostogram was negative for extravasation, so the patient underwent EGD to evaluate for the resolution of the PDF. During the procedure, iohexol contrast and methylene blue were inserted via nephrostomy tube, and fluoroscopic imaging showed contrast in the right kidney and bladder without extravasation. However, on endoscopy, methylene blue extravasation led to identification of two mucosal defects in the anterior duodenal sweep (Image 2). The larger defect was closed using the helix tissue retractor and OTSC system (12/6 t-type) (Image 3). The smaller defect was closed with 2 hemostasis clips. Follow-up renal scan and CT imaging showed no evidence of contrast extravasation. DISCUSSION: The OTSC is an innovative endoscopic technique most often used for hemostasis and for treatment of endoscopic or surgical complications (e.g., fistula, leakage, or perforation). Most reports document successful OTSC use for fistula closure including gastrocutaneous and esophageal fistulas. Our case is, to our knowledge, the second ever documented PDF closure using the OTSC system.