BACKGROUND: I-scan technology is the newly developed endoscopic tool that works in real time and utilizes a digital contrast method to enhance endoscopic image. AIMS: We performed a feasibility study aimed to determine the diagnostic accuracy of i-scan technology for the evaluation of duodenal villous patterns, having histology as the reference standard. METHODS: In this prospective, single center, open study, patients undergoing upper endoscopy for an histological evaluation of duodenal mucosa were enrolled. All patients underwent upper endoscopy using high resolution view in association with i-scan technology. During endoscopy, duodenal villous patterns were evaluated and classified as normal, partial villous atrophy, or marked villous atrophy. Results were then compared with histology. RESULTS: One hundred fifteen subjects were recruited in this study. The endoscopist was able to find marked villous atrophy of the duodenum in 12 subjects, partial villous atrophy in 25, and normal villi in the remaining 78 individuals. The i-scan system was demonstrated to have great accuracy (100 %) in the detection of marked villous atrophy patterns. I-scan technology showed quite lower accuracy in determining partial villous atrophy or normal villous patterns (respectively, 90 % for both items). CONCLUSIONS: Image-enhancing endoscopic technology allows a clear visualization of villous patterns in the duodenum. By switching from the standard to the i-scan view, it is possible to optimize the accuracy of endoscopy in recognizing villous alteration in subjects undergoing endoscopic evaluation.