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If some adenomas do not bleed over several years, they will cause systematic false-negative fecal immunochemical test (FIT) results. The long-term effectiveness of FIT screening has been estimated without accounting for such systematic false-negativity. There are now data with which to evaluate this issue.The authors developed one microsimulation model (MISCAN [MIcrosimulation SCreening ANalysis]-Colon) without systematic false-negative FIT results and one model that allowed a percentage of adenomas to be systematically missed in successive FIT screening rounds. Both variants were adjusted to reproduce the first-round findings of the Dutch CORERO FIT screening trial. The authors then compared simulated detection rates in the second screening round with those observed, and adjusted the simulated percentage of systematically missed adenomas to those data. Finally, the authors calculated the impact of systematic false-negative FIT results on the effectiveness of repeated FIT screening.The model without systematic false-negativity simulated higher detection rates in the second screening round than observed. These observed rates could be reproduced when assuming that FIT systematically missed 26% of advanced and 73% of nonadvanced adenomas. To reduce the false-positive rate in the second round to the observed level, the authors also had to assume that 30% of false-positive findings were systematically false-positive. Systematic false-negative FIT testing limits the long-term reduction of biennial FIT screening in the incidence of colorectal cancer (35.6% vs 40.9%) and its mortality (55.2% vs 59.0%) in participants.The results of the current study provide convincing evidence based on the combination of real-life and modeling data that a percentage of adenomas are systematically missed by repeat FIT screening. This impairs the efficacy of FIT screening. Cancer2016;122:1680-8. © 2016 American Cancer Society.A percentage of adenomas are systematically missed by repeated fecal immunochemical test screening. This impairs the efficacy of fecal immunochemical test screening, although the effect appears to be limited.