Missing adenomas and the inability to accurately differentiate between polyp histology remain the main limitations of standard-definition white-light (SD-WL) colonoscopy. To compare the adenoma detection rates of SD-WL with those of high-definition white-light (HD-WL) and narrow-band imaging (NBI) as well as the accuracy of predicting polyp histology. Multicenter, prospective, randomized, controlled trial. Two academic medical centers in the United States. Subjects undergoing screening or surveillance colonoscopy. Subjects were randomized to undergo colonoscopy with one of the following: SD-WL, HD-WL, or NBI. The proportion of subjects detected with adenomas, adenomas detected per subject, and the accuracy of predicting polyp histology real time. A total of 630 subjects were included. The proportion of subjects with adenomas was 38.6% with SD-WL compared with 45.7% with HD-WL and 46.2% with NBI (P = .17 and P = .14, respectively). Adenomas detected per subject were 0.69 with SD-WL compared with 1.12 with HD-WL and 1.13 with NBI (P = .016 and P = .014, respectively). HD-WL and NBI detected more subjects with flat and right-sided adenomas compared with SD-WL (all P values <.005). NBI had a superior sensitivity (90%) and accuracy (82%) to predict adenomas compared with SD-WL and HD-WL (all P values <.005). Academic medical centers with experienced endoscopists. There was no difference in the proportion of subjects with adenomas detected with SD-WL, HD-WL, and NBI. However, HD-WL and NBI detected significantly more adenomas per subject (>60%) compared with SD-WL. NBI had the highest accuracy in predicting adenomas in real time during colonoscopy. ( NCT 00614770.).