A 61-year-old male who complained of right upper quadrant pain was referred to the authors for evaluation after his computed tomography suggested biliary adenocarcinoma. The lesion consisted of multiple cysts with papillary mass and peri-ampullay mass. The patient underwent an operation due to a clinical suspicion of biliary cystadenocarcinoma, but the pathology confirmed biliary papillomatosis (BP) after diagnosing intrahepatic papillary neoplasm with high-grade dysplasia and invasive adenocarcinoma with papillary neoplasm from the distal common bile duct to the duodenum. BP is a disease characterized by multiple papillary masses. Its cause has yet to be discovered. It commonly manifests as bile duct dilation but rarely as a ductal cystic change. Under computed tomography or magnetic resonance imaging, both the BP and the cystic neoplasm can show bile duct dilation and a papillary mass, which makes their differential diagnosis difficult. A confirmative diagnosis can be made through a pathologic examination. BP is classified as a benign disease that can become malignant and may recur, though rarely. Its treatment of choice is surgical resection. Laser ablation or photodynamic therapy can be used for unresectable lesions. In the case featured in this paper, biliary papillomatosis was difficult to differentiate from cystic adenocarcinoma due to diffusely scattered multiple large cystic lesions in the liver, and it was histologically confirmed to have become malignant with cystic duct dilation after the operation. This case is reported herein with a literature review.