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Purpose: To reduce colorectal cancer morbidity and mortality in Taiwan, a nationwide screening program with fecal immunochemical test was implemented from January 2004. This study evaluated the influence of this screening program through the controlled interrupted time series analysis. Methods: The controlled interrupted time series analysis was performed using the Poisson regression model with simple linear spline function adjusted for 5-year age-groups and the birth cohort. A sensitivity analysis was performed to re-estimate the effect of the screening program. Results: The expected age-adjusted colorectal cancer mortality rates (by setting the effect of the screening program to zero) for both genders were close to the observed rates during 2004–2013 and were dramatically higher than the observed rates thereafter. The average annual percent changes in colorectal cancer mortality revealed an increasing trend for the age-groups 0–49 and ≥ 75 years and a decreasing trend for the age-groups 50–69 and 70–74 years for 2014–2017. Compared with 1991–2003, the adjusted mortality rate ratios were 0.93 (0.86–1.00) and 1.07 (1.00–1.15) in 2014–2017 for the screening and control groups. Regarding the percent changes, reductions of 7.49% between 1991–2003 and 2014–2017 and 14.76% between the control and screening groups were observed. Conclusion: The nationwide screening program effectively reduced colorectal cancer mortality. Including individuals aged 70–74 years into the target population of the screening program as well as including medical centers and clinics in the program to promote the screening test effectively reduced colorectal cancer mortality. [ABSTRACT FROM AUTHOR]