The COLONPREV study is an ongoing multicenter, nationwide, randomized controlled trial aimed at evaluating the efficacy of once-only colonoscopy and biennial fecal immunochemical testing with respect to the reduction of CRC-related mortality at 10 years in average-risk colorectal cancer screening population. Following a pragmatic approach, this study may contribute to establishing the most cost-effective strategy in a programmatic, population-based setting. In this review, we report the results obtained at the first screening round, as well as others achieved in nested evaluations using the COLONPREV dataset with the aim of clarifying some controversial issues on the different strategies of colorectal cancer screening.