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Role of CH-EUS as guidance for EUS-biliary drainage malignant obstruction. Endoscopic ultrasound (EUS)-guided biliary drainage is the usual method of choice for patients with biliary obstructions difficult to treat by endoscopic retrograde cholangiopancreatography. In some patients, however, the bile duct is difficult to detect during EUS-guided biliary drainage. Contrast-enhanced harmonic endoscopic ultrasound has reportedly been useful for interventional EUS procedures. This study describes five patients who underwent EUS-guided biliary drainage with contrast-enhanced harmonic imaging between April 2017 and March 2020 for malignant biliary obstruction due to bile duct cancer. The procedure was performed through an intrahepatic bile duct approach in three patients and through an extrahepatic bile duct approach in the other two. Although fundamental B-mode EUS was unable to detect the target intrahepatic bile duct because the duct was filled with debris, contrast-enhanced harmonic imaging was able to detect the bile duct by clarifying its border with the hepatic parenchyma. Similarly, in patients who underwent extrahepatic bile duct approach, fundamental B-mode EUS could not distinguish between debris and tumor, whereas contrast-enhanced harmonic EUS was able to differentiate between them. The procedure was technically and clinically successful in all five patients. One patient experienced bleeding as an adverse event. Conclusions: EUS-guided biliary drainage with contrast-enhanced harmonic imaging is useful in detecting the fluid space in bile ducts filled with debris or filled with debris and tumor invasion.