Abstract Background The Endocuff Vision device (Arc Medical Design Ltd., Leeds, UK) has been shown to increase mucosal exposure, and consequently adenoma detection rate (ADR), during colonoscopy. This nationwide multicenter study assessed possible benefits and harms of using Endocuff Vision in a fecal immunochemical test (FIT)-based screening program. Methods Patients undergoing colonoscopy after a FIT-positive test were randomized 1:1 to undergo Endocuff-assisted colonoscopy or standard colonoscopy, stratified by sex, age, and screening history. Primary outcome was ADR. Secondary outcomes were ADR stratified by endoscopists’ ADR, advanced ADR (AADR), adenomas per colonoscopy (APC), withdrawal time, and adverse events. Results 1866 patients were enrolled across 13 centers. After exclusions, 1813 (mean age 60.1 years; male 53.8 %) were randomized (908 Endocuff Vision, 905 standard colonoscopy). ADR was significantly higher in the Endocuff Vision arm (47.8 % vs. 40.8 %; relative risk [RR] 1.17, 95 % confidence interval [CI] 1.06–1.30), with no differences between arms regarding size or morphology. When stratifying for endoscopists’ ADR, only low detectors (ADR < 33.3 %) showed a statistically significant ADR increase (Endocuff Vision 41.1 % [95 %CI 35.7–46.7] vs. standard colonoscopy 26.0 % [95 %CI 21.3–31.4]). AADR (24.8 % vs. 20.5 %, RR 1.21, 95 %CI 1.02–1.43) and APC (0.94 vs. 0.77; P = 0.001) were higher in the Endocuff Vision arm. Withdrawal time and adverse events were similar between arms. Conclusion Endocuff Vision increased ADR in a FIT-based screening program by improving examination of the whole colonic mucosa. Utility was highest among endoscopists with a low ADR.