The aim of this study was to evaluate prospectively the efficacy of different imaging methods in differentiating between chronic pancreatitis and cancer in focal pancreatic lesions and staging of adenocarcinoma. MATERIAL AND METHODS. Between June 2005 and October 2007, 156 consecutive patients were enrolled into the prospective clinical trial. The patients were randomized into two groups. Ultrasonoscopy and endoscopic ultrasound were performed in both the groups. Group A patients were additionally examined by computed tomography and tumor marker assay, while in the group B, intraoperative ultrasonoscopy with biopsy and urgent histological examination were done. Results of each imaging technique regarding differential diagnosis and cancer stage were compared with the findings of surgical and histological examination. RESULTS. Chronic pancreatitis and adenocarcinoma were documented in 58 (37.2%) and 78 (50%) patients, respectively. The size of the lesions and clinical presentation were similar in both the groups, but cancer patients were older than patients with pancreatitis (P<0.001). Preoperatively endosonoscopy had the highest accuracy in assessing differential diagnosis (92.1%) and adenocarcinoma (91.8%), whereas computed tomography had the highest accuracy in assessing tumor size (84.5%) and transabdominal ultrasonography in assessing lymph node involvement (78.9%) and distant metastases (88.6%). Intraoperative ultrasound was the most accurate imaging technique in the assessment of differential diagnosis (100%), adenocarcinoma (98.5%), extent of primary tumor (84.8%), lymph node involvement (87.9%), and distant metastases (100%). CONCLUSIONS. In the differential diagnosis between chronic pancreatitis and adenocarcinoma, preoperative ultrasonography and intraoperative ultrasound are the best imaging methods. When ultrasonography is nondiagnostic, computed tomography and endoscopic ultrasound are alternative techniques.