Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are common in colorectal cancers (CRCs). The association between EMAST and classic mono/dinucleotide microsatellite instability (MSI) is unknown. We assessed the stability of 13 tetranucleotide and three pentanucleotide repeat markers in tumor and normal tissue from 22 MSI-high and 107 microsatellite-stable CRC samples. When present, instability was observed at tetra/pentanucleotide repeats and was defined as elevated microsatellite alterations at selected tetra/pentanucleotide repeats-high (EMASTP-H; ≥30% instability), -low (EMASTP-L; <30% instability), or -stable (EMASTP-S). EMASTP instability, including high and low, was observed in 50 of 123 CRCs (41%), including all MSI-high tumors and 28 of 101 microsatellite-stable tumors (28%). MSI-high CRCs were more likely to be EMASTP-H compared with microsatellite-stable tumors with EMASTP instability. Tetranucleotide markers VWA and D13S317 were the two most frequently altered loci. Loss of heterozygosity was more common in EMASTP-L/S than in EMASTP-H CRCs. Frequencies of loss of heterozygosity at three loci were different between EMASTP-L and EMASTP-S tumors. In addition, right-sided tumor site, large tumor size, high tumor grade, and the presence of Crohn-like reaction were significantly associated with EMASTP-H CRCs. However, there were no differences in clinicopathologic features between EMASTP-L and EMASTP-S tumors. In summary, more CRCs exhibited genomic instability as EMASTP than as MSI. EMASTP instability may prove to be an important prognostic/therapeutic indicator in CRCs.