Flexible sigmoidoscopy is recommended for persons at average risk for colorectal cancer. A follow-up is advised in 3 to 5 years, although the outcomes are not well established. We designed a large, prospective study of an unselected population to measure the incidence of advanced adenomas at flexible sigmoidoscopy 3 and 5 years after an initial negative examination. Adenomas were considered advanced if they were villous, tubulovillous, high-grade dysplasia, adenocarcinoma, or ≥10 mm in size. We evaluated 8121 patients referred for flexible sigmoidoscopy and 4010 met the inclusion criteria. Group 1 had flexible sigmoidoscopy between 3 and 4 years and Group 2 between 5 and 6 years after a negative examination. Group 1 included 1300 patients with an incidence rate for advanced adenomas of 0.9% (12/1300) and Group 2 included 2710 patients with an incidence rate for advanced adenomas of 1.1% (30/2710). When the two group were subdivided by the presence or absence of a family history of a first-degree relative with sporadic colorectal cancer, the incidence rates for advanced adenomas between the populations were not different. Our data indicate incidence rates of 0.9 and 1.1% for advanced adenomas at flexible sigmoidoscopy 3 and 5 years, respectively, after a negative flexible sigmoidoscopy, with no impact from a family history.