For difficult cases to diagnose or treat for biliary disease, peroral cholangioscopy (POCS) has clinical benefit. Recently, the digital single-operator cholangioscope (DSOCS) has become available. This system may allow diagnosis by direct visualization and allow performance of various therapeutic procedures. The aim of this study was to prospectively evaluate the clinical utility of the DSOCS for diagnostic and therapeutic procedures for biliary disease. Technical success was defined as successful visualization of target lesions in the biliary tract and performing forceps biopsy as a diagnostic procedure, and successfully performing treatment such as guidewire insertion for the area of interest, electrohydraulic lithotripsy (EHL), or migrated stent removal. Cholangioscopic findings were divided into two groups, according to previous reports: malignant findings: 1) irregular thick tortuous vessels, 2) easy oozing of blood, 3) irregular papillogranular surface, and 4) nodular elevated surface like a submucosal tumor, benign findings: 1) fine network of thin vessels and flat surface with or without shallow pseudodiverticula, 2) lower homogenyous papillogranular surface without primary masses, suggesting hyperplasia, 3) bumpy surface with or without pseudodiverticula, suggesting inflammation, and 4) white surface with convergence of folds, suggesting scar. The present study aimed at investigating diagnostic yield of the cholangioscopic findings and biopsy specimens. The present study was primarily aimed at investigating technical feasibility and safety of SPY-DS for diagnostic and therapeutic procedures. Secondly, the present study was aimed at investigating diagnostic yield such as sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of the cholangioscopic findings and biopsy specimens compared with that of the final diagnosis. A total of 55 consecutive patients were prospectively enrolled in this study; a diagnostic procedure was performed in 33 patients, and a therapeutic procedure was performed in 22 patients. The overall accuracy of visual findings was 93%, with a sensitivity of 83%, a specificity of 89%, PPV of 83%, and NPV of 100%. However, the overall accuracy of forceps biopsy was 89%, with a sensitivity, specificity, and PPV of 100%, and NPV of 90%. The overall technical success rate of therapeutic procedures such as selective guidewire insertion, EHL or migrated stent removal was 91% (20/22). Finally, adverse events were seen in two cases in diagnostic group, and were not seen in therapeutic group. Although additional cases and a randomized, controlled study with another cholangioscope are needed, diagnostic and therapeutic procedures using SPY-DS appear to be feasible and safe.