Background The newly developed i-SCAN application can theoretically maximize the effectiveness of colonoscopy. However, the practical usefulness of the i-SCAN application during screening colonoscopy has not been assessed. Objective To assess the efficacy of the i-SCAN application during screening colonoscopy. Design A prospective, randomized trial that used a modified, back-to-back colonoscopy. Setting Academic hospital. Patients This study involved 389 asymptomatic, consecutive, average-risk patients who underwent screening colonoscopy. Intervention The patients were randomized to the first withdrawal with either conventional high-definition white light (HDWL group; n = 119), i-SCAN contrast/surface enhancement (CE/SE) mode (i-SCAN1 group; n = 115), or i-SCAN CE/SE/tone enhancement-colorectal mode (i-SCAN2 group; n = 118). All patients underwent a second examination with HDWL as the criterion standard. Main Outcome Measurements The primary outcome measurement was the adenoma detection rate and adenoma miss rate. The secondary outcome measurement was the accuracy of the histologic prediction of neoplastic and nonneoplastic polyps. Results The adenoma detection rates during the first withdrawal of HDWL, i-SCAN1, and i-SCAN2 were 31.9%, 36.5%, and 33.1%, respectively ( P = .742), and the adenoma miss rates of each group were 22.9%, 19.3%, and 15.9%, respectively ( P = .513). Based on the multivariate analysis, the application of i-SCAN was not associated with an improvement in adenoma detection and the prevention of missed polyps. However, the prediction of neoplastic and nonneoplastic colorectal lesions was more precise in the i-SCAN2 group compared with the HDWL group (accuracy 79.3% vs 75.5%, P = .029; sensitivity 86.5% vs 72.6%, P = .020; and specificity 91.4% vs 80.6%, P = .040). Limitations Single-center trial. Conclusion i-SCAN during the screening colonoscopy may fail to improve adenoma detection and the prevention of missed polyps, but i-SCAN appears to be effective for real-time histologic prediction of polyps compared with conventional HDWL colonoscopy. (Clinical trial registration number: NCT01417611 .)