Replication error deficient (RER+) colorectal cancers are a distinct subset of colorectal cancers, characterized by inactivation of the DNA mismatch repair system. These cancers are typically pseudodiploid, accumulate mutations in repetitive sequences as a result of their mismatch repair deficiency, and have distinct pathologies. Regulatory sequences controlling all aspects of mRNA processing, especially including message stability, are found in the 3′UTR sequence of most genes. The relevant sequences are typically A/U-rich elements or U repeats. Microarray analysis of 14 RER+ (deficient) and 16 RER− (proficient) colorectal cancer cell lines confirms a striking difference in expression profiles. Analysis of the incidence of mononucleotide repeat sequences in the 3′UTRs, 5′UTRs, and coding sequences of those genes most differentially expressed in RER+ versus RER− cell lines has shown that much of this differential expression can be explained by the occurrence of a massive enrichment of genes with 3′UTR T repeats longer than 11 base pairs in the most differentially expressed genes. This enrichment was confirmed by analysis of two published consensus sets of RER differentially expressed probesets for a large number of primary colorectal cancers. Sequence analysis of the 3′UTRs of a selection of the most differentially expressed genes shows that they all contain deletions in these repeats in all RER+ cell lines studied. These data strongly imply that deregulation of mRNA stability through accumulation of mutations in repetitive regulatory 3′UTR sequences underlies the striking difference in expression profiles between RER+ and RER− colorectal cancers.