The natural history of untreated colonic polyps is uncertain. A retrospective review of Mayo Clinic records from a 6-yr period just before the advent of colonoscopy identified 226 patients with colonic polyps greater than or equal to 10 mm in diameter in whom periodic radiographic examination of the colon was elected over excisional therapy. In all patients, follow-up of polyps spanned at least 12 mo (mean, 68 mo; range, 12-229 mo) and included at least two barium enema examinations (mean, 5.2; range, 2-17). During the follow-up period, 83 polyps (37%) enlarged. Twenty-one invasive carcinomas were identified at the site of the index polyp at a mean follow-up of 108 mo (range, 24-225 mo). Actuarial analysis revealed that the cumulative risk of diagnosis of cancer at the polyp site at 5, 10, and 20 yr was 2.5%, 8%, and 24%, respectively. In addition, 11 invasive cancers were found at a site remote from the index polyp during the same follow-up period. These data further support the recommendation for excision of all colonic polyps greater than or equal to 10 mm in diameter. Periodic examination of the entire colon is recommended in this group of patients to identify neoplasms arising at a site remote from the index polyp. Although this study has limitations inherent to any retrospective analysis, comparable prospective data are unlikely to be available in the future because of the current widespread availability of colonoscopy.