Over-expression and abnormal intracellular location of the product of the oncogene c-myc in colonic dysplasia and neoplasia may be related to alterations in epigenetic mechanisms controlling the functioning of this gene. We have investigated the methylation patterns of the c-myc oncogene in human colorectal tissue representing various stages of dysplasia and neoplasia, including metastasis to liver, omentum and lymph node. Comparison of normal and neoplastic tissues from the same patient showed a decrease in methylation in a specific CCGG site in the third exon of c-myc through the progression from normal via dysplastic to neoplastic and metastatic tissue. Quantitative analysis revealed that in colonic adenocarcinomas an average of 66.1% and in metastatic deposits 83.1% of the myc gene DNA was hypomethylated at this site, as compared to a value of 9.2% in normal colonic mucosa. Adenomatous polyps showed an average value of 50.5% and hyperplastic polyps, 24.8%. The results suggest that partial hypomethylation of the c-myc gene third exon is associated with cell proliferation, and that deregulation of proliferation may be linked to the high levels of hypomethylation, presumably involving both copies of the gene in some cells, which occur at a relatively early stage in neoplastic progression.