Mutations in the transforming growth factor-beta type II receptor (RII) gene that remain uncorrected due to mutation and inactivation of mismatch repair genes play an important role in hereditary nonpolyposis colorectal cancer (HNPCC) and in a subset of sporadic colorectal cancers. Some colorectal cancers develop from colorectal polyps. To elucidate the role of the RII gene in the generation of colorectal polyps, we analyzed 137 colorectal polyps from 100 patients for RII mutations and microsatellite instability (MSI). MSI was detected in three of 36 polyps from 25 patients. For one of these three polyps, the mobilities of the PCR products between polyp and nonpolyp tissues was different for only one microsatellite marker, and for the other two polyps the mobilities were different for more than two markers. These two polyps were obtained from one patient with ascending colon carcinoma and suspected HNPCC based on his clinical profile and family history. An RII mutation was detected in only one of these two polyps. RII may play a minor role in sporadic colorectal polyps. RII gene analysis in colorectal polyps may be a useful screening measure for potential HNPCC patients.