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Background Real-time optical diagnosis of colorectal polyps may lead to substantial time and cost savings and could potentially reduce complications associated with polypectomy. We prospectively assessed the utility of a novel narrow-band imaging (NBI) system with dual focus magnification (DF) in differentiating colorectal polyps in consecutive patients undergoing colonoscopy. Patients and Methods All procedures were carried out with a prototype 190 series Exera III NBI system with Dual Focus capability. Histology of each polyp was predicted in real time with NBI-DF based on the modified Sano's classification with a confidence level (low/high). NBI-DF diagnosis was then compared to the final (blinded) histopathology results. Primary endpoint was the accuracy of endoscopic prediction with the modified Sano's classification of all polyps when they were diagnosed with high confidence. Secondary endpoints were the accuracy of post-polypectomy surveillance intervals for diminutive polyps(≤5 mm). A total of 164 polyps in 87 patients (53 males) with a mean age of 63 (range 28–86) years were evaluated. Results 149 polyps were diagnosed with high confidence on endoscopic prediction, out of which 80 were diminutive, 31 small (6–9 mm) and 38 large (>10 mm). Overall accuracy of NBI-DF compared to final histopathology was 97%. The accuracy for post-polypectomy surveillance interval based on the endoscopic prediction was 97%. The NPV for diminutive rectosigmoid polyps for adenomatous histology was 100%. Conclusion In this preliminary feasibility study, NBI-DF permitted prediction of histology of colorectal polyps with high accuracy. In addition, both of the secondary endpoints exceeded the ASGE PIVI thresholds for the management of diminutive polyps.