Widespread mutations in simple tandemly repeated (STR) DNA sequences are frequently found in colorectal tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) and less frequently in sporadic colorectal cancers. This aims of this study were to determine the type of DNA sequence most commonly affected by such mutations and to examine the point in the natural history of the tumor where replication errors (RERs) appear. An unselected series of colorectal tumors (49 adenomas and 108 carcinomas) was examined with 4 different STR markers: one Alu VpA polymorphism (MYCLI), one tetranucleotide repeat (D17S846), one dinucleotide repeat (D3S1029), and one polyA repeat (AP delta 3 delta). All 3 positive adenomas and 18 of 20 positive carcinomas showed replication errors in the Alu VpA sequence at the MYCLI locus, making this marker more than twice as sensitive as the best of the other 3 markers. Importantly, all positive adenomas showed small foci of carcinoma in situ. This suggests that replication errors manifest at the adenoma/carcinoma transition in sporadic colorectal tumors.