BACKGROUND The effectiveness of fecal immunochemical testing (FIT) in reducing colorectal cancer (CRC) mortality has not yet been fully assessed in a large, population‐based service screening program. METHODS A prospective cohort study of the follow‐up of approximately 5 million Taiwanese from 2004 to 2009 was conducted to compare CRC mortality for an exposed (screened) group and an unexposed (unscreened) group in a population‐based CRC screening service targeting community residents of Taiwan who were 50 to 69 years old. Given clinical capacity, this nationwide screening program was first rolled out in 2004. In all, 1,160,895 eligible subjects who were 50 to 69 years old (ie, 21.4% of the 5,417,699 subjects of the underlying population) participated in the biennial nationwide screening program by 2009. RESULTS The actual effectiveness in reducing CRC mortality attributed to the FIT screening was 62% (relative rate for the screened group vs the unscreened group, 0.38; 95% confidence interval, 0.35‐0.42) with a maximum follow‐up of 6 years. The 21.4% coverage of the population receiving FIT led to a significant 10% reduction in CRC mortality (relative rate, 0.90; 95% confidence interval, 0.84‐0.95) after adjustments for a self‐selection bias. CONCLUSIONS This large, prospective Taiwanese cohort undergoing population‐based FIT screening for CRC had the statistical power to demonstrate a significant CRC mortality reduction, although the follow‐up time was short. Although such findings are informative for health decision makers, continued follow‐up of this large cohort will be required to estimate the long‐term impact of FIT screening if the covered population is expanded. Cancer 2015;121:3221–3229. © 2015 American Cancer Society. A significant reduction in colorectal cancer mortality resulting from fecal immunochemical testing is demonstrated by a large, population‐based, nationwide service screening program with a maximum follow‐up of 6 years. Although long‐term follow‐up of this nationwide service screening program is required, these findings are useful for convincing health decision makers that the continuous promotion of such a nationwide screening program is worthwhile.