AIM: To investigate the distribution of DNA microsatellite instability (MSI) in a series of hyperplastic polyps, serrated adenomas, and mixed polyps of the colorectum. METHODS: DNA was extracted from samples of 73 colorectal polyps comprising tubular adenomas (23), hyperplastic polyps (21), serrated adenomas (17), and mixed polyps (12). The presence of MSI was investigated at six loci: MYCL, D2S123, F13B, BAT-40, BAT-26, and c-myb T22, using polymerase chain reaction based methodology. MSI cases were classified as MSI-Low (MSI-L) and MSI-High (MSI-H), based on the number of affected loci. RESULTS: The frequency of MSI increased in tubular adenomas (13%), hyperplastic polyps (29%), serrated adenomas (53%), and mixed polyps (83%) (Wilcoxon rank sum statistic, p < 0.001). Hyperplastic epithelium was present in nine of 12 mixed polyps and showed MSI in eight of these. MSI was mostly MSI-L. MSI-H occurred in two serrated adenomas and three mixed polyps. Clonal relations were demonstrated between hyperplastic and dysplastic epithelium in four of eight informative mixed polyps. CONCLUSIONS: The findings support the view that hyperplastic polyps may be fundamentally neoplastic rather than hyperplastic. A proportion of hyperplastic polyps may serve as a precursor of a subset (10%) of colorectal cancers showing the MSI-L phenotype, albeit through the intermediate step of serrated dysplasia. This represents a novel and distinct morphogenetic pathway for colorectal cancer.