Background: Periampullary neoplasms can be challenging to work up and diagnose preoperatively. Herein, we report the case of a patient whose preoperative workup failed to detect a malignancy, yet, underwent a pylorus-preserving pancreaticoduodenectomy (PPPD) with intraoperative pancreatic ductoscopy (IPD) and was ultimately found to have an ampullary adenocarcinoma. Presentation: A 78-year-old woman presented with 4 weeks of nausea, weight loss, jaundice, and light-colored stools. She underwent outpatient diagnostic studies, including magnetic resonance cholangiopancreatography, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography with pancreatic duct (PD) stenting and papillotomy. These revealed common bile duct dilatation measuring 2 cm, PD dilatation measuring 7 mm, a 17 mm cyst in the head of the pancreas, and a firm nodule noted between the biliary and pancreatic orifices. Cytologic and pathologic analyses were initially nondiagnostic. A repeat ampullary biopsy was negative for dysplasia and malignancy. A computed tomography scan was then performed and showed cystic pancreatic lesions with pancreatic ductal dilation. Suspicion remained high for periampullary tumor or a main duct intraductal papillary mucinous neoplasm, and the patient underwent a PPPD with IPD and tolerated the procedure well. Her final specimen pathology revealed well-to-moderately differentiated ampullary adenocarcinoma, pancreaticobiliary type with positive nodal disease. Conclusions: Given the relatively poor prognosis of patients with node-positive pancreaticobiliary-type ampullary adenocarcinoma, clinical suspicion should remain high for malignancy in patients with lesions located in the periampullary region and a negative preoperative workup, as aggressive treatment approaches are warranted to maximize their chance for survival.