Hyperplastic polyps are common benign lesions of uncertain histogenesis, which occur in the colon in populations at risk for colorectal carcinoma. They contain neutral/MUC1 gene-related mucin which in turn is closely associated with the trefoil-peptide pS2, a major component of the ulcer-associated cell lineage, previously termed pseudopyloric metaplasia. We have examined 17 hyperplastic polyps for expression of the trefoil-peptides pS2 and human spasmolytic polypeptide by in situ hybridization and immunohistochemistry, as well as by using antisera to epidermal growth factor/urogastrone and its receptor and to epitopes of the product of the MUC1 gene to characterize any further similarity between these lesions and the ulcer-associated cell lineage and thus help elucidate the nature of the lesions. Our investigations show both human spasmolytic polypeptide and pS2 messenger RNA within the polyps, whereas only pS2 peptide could be demonstrated immunohistochemically. Epidermal growth factor/urogastrone, its receptor, and antisera to the MUC1 gene also showed widespread staining of these polyps. We suggest that hyperplastic polyps are formed of a lineage that both synthesizes and secretes trefoil-peptides and the MUC1 mucin and that hyperplastic polyps may be related to the phenotypically similar ulceration-associated cell lineage.