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Flat and depressed colon neoplasms are an increasingly recognized precursor for colorectal cancer (CRC) in Western populations. High-definition chromoscopy is used to increase the yield of colonoscopy for flat and depressed neoplasms; however, its role in average-risk patients undergoing routine screening remains uncertain.Average-risk patients referred for screening colonoscopy at four U.S. medical centers were randomized to high-definition chromocolonoscopy or high-definition white light colonoscopy. The primary outcomes, patients with at least one adenoma and the number of adenomas per patient, were compared between the two groups. The secondary outcome was patients with flat or depressed neoplasms, as defined by the Paris classification.A total of 660 patients were randomized (chromocolonoscopy: 321, white light: 339). Overall, the mean number of adenomas per patient was 1.2±2.1, the mean number of flat polyps per patient was 1.4±1.9, and the mean number of flat adenomas per patient was 0.5±1.0. The number of patients with at least one adenoma (55.5% vs. 48.4%, absolute difference 7.1%, 95% confidence interval (−0.5% to 14.7%),P=0.07), and the number of adenomas per patient (1.3±2.4 vs. 1.1±1.8,P=0.07) were marginally higher in the chromocolonoscopy group. There were no significant differences in the number of advanced adenomas per patient (0.06±0.37 vs. 0.04±0.25,P=0.3) and the number of advanced adenomas <10 mm per patient (0.02±0.26 vs. 0.01±0.14,P=0.4). Two invasive cancers were found, one in each group; neither was a flat neoplasm. Chromocolonoscopy detected significantly more flat adenomas per patient (0.6±1.2 vs. 0.4±0.9,P=0.01), adenomas <5 mm in diameter per patient (0.8±1.3 vs. 0.7±1.1,P=0.03), and non-neoplastic lesions per patient (1.8±2.3 vs. 1.0±1.3,P<0.0001).High-definition chromocolonoscopy marginally increased overall adenoma detection, and yielded a modest increase in flat adenoma and small adenoma detection, compared with high-definition white light colonoscopy. The yield for advanced neoplasms was similar for the two methods. Our findings do not support the routine use of high-definition chromocolonoscopy for CRC screening in average-risk patients. The high adenoma detection rates observed in this study may be due to the high-definition technology used in both groups.