We investigated the magnitude and temporal patterns of the decreasing trend in main performance measures of fecal immunochemical test (FIT) screening for colorectal cancer (CRC) being observed in second and subsequent rounds.We followed 494,187 participants from the first round of a regional biennial FIT screening program in Italy (cut-off value for positivity, 20 μg Hb/g feces) for 5 total rounds (2005-2016). At each round, only compliant participants were eligible. Performance measures from the first, third, fourth, and fifth round were compared with those from the second round (the first incidence round) using rate ratios from multivariate Poisson regression models and relative risk ratios from multinomial logistic regression models.Between the second and the third round, a significant 20-30% decrease was found in the proportion of men with a positive FIT result (from 5.2 to 4.3%) and in detection rates of advanced adenoma (from 13.4 to 10.2 per 1000), CRC (from 1.7 to 1.4 per 1000), and advanced neoplasia (from 15.1 to 11.6 per 1000). Positive predictive values (PPVs) decreased by 10% or less between the second and third rounds. Detection rates and PPVs for adenoma stabilized by the fourth and fifth rounds. The PPVs for advanced adenoma, CRC, and advanced neoplasia decreased slightly, in men and women, by the fourth and fifth rounds. The detection rate of proximal colon cancer stabilized after the second round, whereas the detection rate of distal CRC decreased until the fourth round in men (from 0.7 to 0.3 per 1000) and the fifth round in women.These findings support the notion that FIT screening prevents progression of a subset of advanced adenomas. Screening intensity could be modulated based on results from previous rounds, with a risk-based strategy.