Purpose Fecal tests remain a mainstay of population-based colorectal cancer (CRC) screening programs worldwide. However, data on interval CRC (iCRC) arising after follow-up colonoscopy of a positive fecal test are scarce. We conducted a nationwide population-based study to reveal the risk and characteristics of iCRC in this setting.Materials and Methods We searched the National Cancer Screening Program for CRC database in Korea (2005-2010). Incidence of iCRC within the program was estimated, then Cox proportional-hazards regression analysis was performed to determine the independent predictors of iCRC. The clinical characteristics of iCRC were compared with screen-detected CRC (sCRC).Results We identified 280 iCRC among 150,660 negative colonoscopies as a follow-up exam to a positive fecal immunochemical test (FIT), and 2,427 sCRC. The overall incidence of iCRC was 0.49/1,000 person-years (95% confidence interval [CI], 0.48 to 0.51). iCRC was more likely to occur in men (adjusted hazard ratio [aHR], 1.79; 95% CI, 1.39 to 2.30) and elderly patients (aHR, 1.77; 95% CI, 1.38 to 2.28 in 65-74 years; aHR, 3.13, 95% CI, 2.13 to 4.60 in ≥ 75 years). The National Quality Improvement Program for colonoscopy reduced a short-term risk of iCRC (aHR, 0.48; 95% CI, 0.27 to 0.87). Compared with sCRC, iCRC was more likely to occur in the proximal colon, be diagnosed at the localized stage, and have a lower CRC mortality (32.7 vs. 17.4%, 56.8 vs. 34.1%, and 12.5 vs. 17.7%, respectively; all p < 0.05).Conclusion In a population-based CRC screening program with FIT, the burden of iCRC after follow-up colonoscopy was substantial. Men and elderly patients possess a significantly higher risk of iCRC.