Background/Aims: The differential diagnosis of pancreatic solid lesions remains challenging. The aim of this study was to investigate the accuracy of contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) in differentiating pancreatic cancer from benign lesions. Methods: We prospectively evaluated 37 patients with pancreatic solid lesions. After intravenous injection of a contrast agent (SonoVue), CEH-EUS was performed using a radial echoendoscope. Pancreatic solid lesions were classified into three vascular patterns (hyperintense, isointense, and hypointense) on the basis of CEH-EUS imaging, and these patterns were compared to the histological diagnosis. Results: The lesions were hypervascular (n=6), isovascular (n=3), or hypovascular (n=28). Histological diagnosis was confirmed by EUS-FNA in 26 patients (22 adenocarcinomas, two focal pancreatitis, one pancreatic neuroendocrine tumor [NET], and one pancreatic tuberculosis), by surgery in 10 patients (four adenocarcinomas, three pancreatic NETs, two invasive intraductal papillary mucinous neoplasms, and one acinar cell carcinoma), and by both methods in one patient. Among pancreatic carcinomas, 28 out of 30 lesions (93%) had persistent hypovascular signals in the early and late phase, which indicates a sensitivity and diagnostic accuracy of 93% and 92%, respectively for the diagnosis of pancreatic cancer. Conclusions: CEH-EUS was useful for characterization of pancreatic solid masses with high sensitivity and accuracy. (Gut Liver 2013,7:599-604)