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Hyperplastic polyps are usually considered to be an innocent finding with little or no potential to progress to colorectal cancer. However, recent literature suggests that some of these polyps may be morphologically and genetically distinct and lead to microsatellite unstable colorectal cancers. The purpose of this study was to define the cancer risk associated with hyperplastic polyposis.All patients with hyperplastic polyposis diagnosed by a single colorectal surgeon at a university hospital were followed prospectively. The diagnosis of hyperplastic polyposis was made by the presence of more than 20 hyperplastic polyps distributed throughout the colon and/or a hyperplastic polyp at least 1 cm in size in diameter in the right colon. Patient demographics, family history, size, location, and distribution of polyps and the development of colorectal cancer were noted.Thirteen patients who met the criteria for hyperplastic polyposis were identified and followed prospectively. All of these patients had at least 30 polyps distributed throughout the colon, often > 100. Nine of 13 also had a hyperplastic polyp at least 1 cm in size, usually in the right colon. Of particular note, 7 of 13 patients (54 percent) were diagnosed with colorectal cancer during the study period. Four had cancer on initial diagnosis and three patients developed cancer despite frequent colonoscopic surveillance. Five of seven colorectal cancers were located in the right colon.Patients with hyperplastic polyposis are at high risk for colorectal cancer. Failure to identify this subset of patients could have dire consequences.