The SpyGlass (Boston Scientific, Marlborough, Mass, USA) single-operator cholangioscopy (SOC) system is generally considered to be safe but adds additional risks to those associated with standard ERCP. We evaluated adverse events (AEs) associated with the SpyGlass system reported in the U.S. Food and Drug Administration Manufacturer and User Facility Device Experience database between January 2016 and August 2023. From the database, 2311 device problems (SpyGlass DS, 1301; SpyGlass DS II, 1010) were reported. An optical problem was the most reported issue (SpyGlass DS, 83; SpyGlass DS II, 457). Patient-related events were found in 62 of 1743 reports (3.5%): 33 with the SpyGlass DS and 29 with the SpyGlass DS II. The most common AEs were bleeding/hemorrhage followed by perforation; infection, fever, or sepsis; and pancreatitis. Our findings add to the existing literature and provide a fuller picture of potential problems associated with the SpyGlass SOC.