A transformation in the composition of colonic glycoconjugates has been described in adenomas, carcinomas, and certain premalignant conditions. These changes have been detected histochemically by the labeling patterns of fluorescein-conjugated lectins, which bind specific carbohydrate structures on fixed tissue sections. This study was performed to determine whether abnormal lectin binding patterns are present in tissues from patients genetically predisposed to colonic neoplasms and whether these patterns could be used as phenotypic markers for inheritance of the genotype. Lectin staining patterns of 22 colectomy specimens from patients with familial polyposis coli (FPC) and rectal biopsy specimens from 47 patients at risk for hereditary nonpolyposis colorectal cancer (HNPCC) (also known as Lynch syndromes I and II) were compared with rectal biopsy specimens from 27 sex-matched controls. The fluorescein-conjugated lectins included the agglutinins derived from peanut, Dolichos biflorus, Ulex europeus, and wheat germ (including the succinylated derivative). Using a technique for quantitating lectin binding on the tissue sections that provided a score from 0 to 400, labeling with certain lectins was found to vary slightly as a function of age and sex. Histologically normal mucosa from patients with FPC bound significantly less wheat germ agglutinin but significantly more U. europeus and succinylated wheat germ agglutinins than controls. Adenomas and dysplastic flat mucosa from the colectomy specimens of patients with FPC showed significantly less binding with D. biflorus, succinylated wheat germ, and wheat germ agglutinins than controls. Rectal tissues from patients at risk for HNPCC were found to bind significantly less peanut agglutinin and D. biflorus agglutinin than controls. Of interest, staining of the tissues by peanut and wheat germ lectins increased as a function of patient age; the control subjects were older than the patients with familial colon cancer, which could possibly account for the observations made with these two lectins. These results provide evidence that the premalignant colonic epithelium in familial polyposis and the hereditary nonpolyposis colon cancer syndromes may be biologically different and indicate that glycoconjugate modifications are early events in the evolution of the neoplastic phenotype.