Although cholangiocarcinomas (CCAs) can be diagnosed using several modalities, the detection of early-stage cancers remains unsatisfactory. We explored whether peroral cholangioscopy (POC) could be used to screen for neoplastic bile duct lesions including CCAs in patients with bile duct stones. Two hundred seven patients who underwent endoscopic removal of bile duct stones were enrolled between August 2010 and July 2018. The primary outcome was the detection rate of intraductal neoplastic biliary lesions by direct POC. Secondary outcomes were the technical success rates of direct POC and POC-guided forceps biopsy sampling (POC-FB), the diagnostic accuracy of the direct POC findings, adverse events, and the number needed to screen to detect a neoplastic bile duct lesion. Direct POC was successful in 199 of 207 patients (96.1%). Mild cholangitis developed in 2 patients (1.0%) and was treated conservatively. Of the 199 successfully performed POCs, 31 patients (15.6%) exhibited abnormal intraductal mucosal lesions. The technical success rate of POC-FB was 90.3% (28/31 patients). The pathologic diagnoses after POC-FB were CCAs (n= 4), intraductal papillary neoplasms of the bile duct (IPN-B) (n= 2), an adenoma with dysplasia (n= 1), and benign lesions (n= 21). Direct POC correctly distinguished non-neoplastic from neoplastic bile duct lesions in 91.6% of patients. Curative surgical resection was performed for the 5 patients with CCAs or IPN-B. The number needed to screen to detect a neoplastic bile duct lesion was 29.6. Direct POC using a dedicated, ultraslim upper endoscope usefully screens for neoplastic bile duct lesions including CCAs in selected patients with bile duct stones.