Endoscopic ultrasound is a widely accepted imaging method for staging of ductal adenocarcinoma and the localization of neuroendocrine tumors of the pancreas. We prospectively evaluated conventional color Doppler imaging and contrast-enhanced endoscopic Doppler ultrasound (CE-EDUS) as a new imaging technique for further characterization and differentiation of solid pancreatic tumors. From 300 patients with pancreatic lesions investigated using contrast-enhanced endoscopic ultrasound we could finally include 93 patients with an undetermined, solitary, predominantly solid, lesion 40 mm or less, and a definite histologically proven diagnosis. After bolus injection of the contrast agent SHU 508A 4 g (400 mg/dL) the vascular pattern of the lesion during the arterial phase was compared with the vascularity of the residual pancreatic parenchyma. Color Doppler imaging did not reveal vascularity of the pancreatic parenchyma in any of the patients, and therefore tumor hypovascularity could not be determined in contrast to all CE-EDUS-examined patients revealing at least some degree of parenchymal vascularity. Fifty-seven of 62 patients with ductal adenocarcinoma of the pancreas showed a hypovascularity of the tumor using CE-EDUS. All other pancreatic lesions revealed an isovascular or hypervascular pattern using contrast-enhanced endoscopic ultrasound (20 neuroendocrine tumors, 10 serous microcystic adenomas, and 1 teratoma). Hypovascularity as a sign of malignancy in contrast-enhanced endoscopic ultrasound obtained 92% (82%-97%) sensitivity and 100% specificity (89%-100%). Contrast-enhanced endoscopic ultrasound is effective in differentiating small solid pancreatic tumors of different origin in most cases. Hypovascularity indicates malignancy of pancreatic tumors.