OBJECTIVE Contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) for the assessment of microcirculation and the delineation of pancreatic tumors in order to characterize and stage them has only recently become available for commercial use, and few reports have been published. The purpose of the study was the qualitative and quantitative digital image analysis of pancreatic adenocarcinomas using conventional endoscopic ultrasonography (EUS) and CEH-EUS and the evaluation of whether contrast medium injection modified adenocarcinoma staging and patient management. METHODS In each of 30 prospectively examined patients with suspected pancreatic solid lesions, CEH-EUS was performed using the same quantity of the contrast agent SonoVue and a low mechanical index (0.3 - 0.4), followed by EUS-FNA. The histology, based on EUS-FNA or surgery and 9 months of follow-up, was: pancreatic adenocarcinoma (n = 15), pseudotumoral chronic pancreatitis (n = 12), neuroendocrine tumor (n = 1), common bile duct tumor (n = 1), lymph node metastases of gastric cancer (n = 1). The quantitative analysis was based on histograms obtained from each CEH-EUS video recording. RESULTS CEH-EUS showed a hypoenhanced pattern in 14 cases of adenocarcinoma and in 10 cases of chronic pancreatitis. The index of the contrast uptake ratio was significantly lower in adenocarcinoma than in mass-forming chronic pancreatitis. A cut-off uptake ratio index value of 0.17 for diagnosing adenocarcinoma corresponded to an AUC (CI 95%) of 0.86 (0.67 - 1.00) with a sensitivity of 80%, a specificity of 91.7%, a positive predictive value of 92.8%, and a negative predictive value of 78%. The size of the pancreatic mass was assessed significantly more effectively by CEH-EUS but adenocarcinoma staging was not modified. CONCLUSIONS The majority of cases of both pancreatic adenocarcinoma and chronic pancreatitis were hypoenhanced and visual discrimination was not possible. This is the first study about CEH-EUS for the quantitative assessment of uptake after contrast injection which has shown that it can aid differentiation between benign and malignant masses but cannot replace EUS-FNA. Neither tumor stage nor therapeutic management have changed after contrast medium injection during CEH-EUS.