Altered mucin glycosylation occurs in colonic adenomas and can correlate with risk for malignant transformation. The purpose of this study was to determine if immunoreactivity of core tandem repeat peptides of specific mucin genes correlates with histopathologic criteria of malignant potential in the colon. Expression of MUC1, MUC2, and MUC3 core tandem repeat proteins was examined in specimens of normal mucosa (n = 20), hyperplastic polyps (n = 10), adenomatous polyps (n = 89), and invasive cancer (n = 19). An immunohistochemical scoring system that takes into account specimen heterogeneity and yields an integrated numerical score subject to statistical analysis was used. RNA message levels from tubular and tubulovillous adenomas (n = 13), normal colon (n = 12), and moderately differentiated adenocarcinomas (n = 8) were determined using RNA slot blot analysis with mucin-specific cDNA probes. MUC1 staining was rarely present in normal colon. MUC2 immunoreactivity was limited to goblet cells in most normal colonic crypts, and MUC3 staining was weakly expressed in the upper crypt regions only. In comparison with normal and hyperplastic specimens, MUC1 and MUC3 immunoreactivity scores were significantly increased in adenomas of increasing villous histology, size, and dysplasia. MUC2 scores were significantly increased in adenomas of greater villous histology and size. Comparable MUC1, MUC2, and MUC3 mRNA levels were present in adenomas and normal colon, whereas mucin mRNA levels were decreased in adenocarcinomas. We conclude that enhanced immunoreactivity of MUC1, MUC2 and MUC3 mucin tandem repeats occurs in adenomatous polyps and is associated with an increased risk for malignant transformation.