Although a split regimen of bowel preparation has been associated with higher levels of bowel cleansing, it is still uncertain whether it has a favourable effect on the adenoma detection rate (ADR). The present study was aimed at evaluating whether a split regimen was superior to the traditional 'full-dose, day-before' regimen in terms of ADR. In a multicentre, randomised, endoscopist-blinded study, 50-69-year-old subjects undergoing first colonoscopy after positive-faecal immunochemical test within an organised colorectal cancer organised screening programmes were 1:1 randomised to receive low-volume 2-L polyethylene glycol (PEG)-ascorbate solution in a 'split-dose' (Split-Dose Group, SDG) or 'day-before' regimen (Day-Before Group, DBG). The primary endpoint was the proportion of subjects with at least one adenoma. Secondary endpoints were the detection rates of advanced adenomas and serrated lesions at per-patient analysis and the total number of lesions. 690 subjects were included in the study. At per-patient analysis, the proportion of subjects with at least one adenoma was significantly higher in the SDG than in the DBG (183/345, 53.0% vs 141/345, 40.9%, relative risk (RR) 1.22, 95% CI 1.03 to 1.46); corresponding figures for advanced adenomas were 26.4% (91/345) versus 20.0% (69/345, RR 1.35, 95% CI 1.06 to 1.73). At per-polyp analysis, the total numbers of both adenomas and advanced adenomas per subject were significantly higher in the SDG (1.15 vs 0.8, p <0.001; 0.36 vs 0.22, p<0.001). In an organised screening setting, the adoption of a split regimen resulted into a higher detection rate of clinically relevant neoplastic lesions, thus improving the effectiveness of colonoscopy. Based on such evidence, the adoption of a split regimen for colonoscopy should be strongly recommended. NCT02178033.