Mismatch repair system is required for the cell to accurately copy its genome during cellular proliferation. Deficiencies of this system result in mutation rates 100-fold greater than those observed in normal cells [1, 2]. These mutations are particularly evident in microsatellite sequences, consisting of repeats of 1–4 bp. Microsatellite instability (MSI) is thereby a hallmark of mismatch repair gene (MMR)-deficient cancers. MSI is found in 77 percent of CRCs from patients with hereditary nonpolyposis colorectal cancer (HNPCC) [3, 4]. MSI is similarly found in approximately 15–20% of sporadic colon cancers that arise in individuals without any family history of colon cancer [3–7]. Both types of MSI(+) tumors share distinct phenotypic features such as preferential localization in the right- sided colon, histological features of poorly differentiated adenocarcinomas or mucinous carcinomas and relatively favorable prognosis [8-11] HNPCC generally is associated with germ-line mutations in one of two MMR genes, hMLH1 and hMSH2, with mutations of other MMR genes being rare [12,13]. The same genes are often mutationally inactivated also in MSI cancers from patients without HNPCC. However, in a significant subset of sporadic tumors with MSI, no mutations of MMR genes could be identified [14-18] and it was speculated that nonmutational mechanisms or novel genes were responsible for the defect [17, 18]. Alternative models of inactivation of genes during the development of cancer include an epigenetic process marked by hypermethylation of the promoter region associated with transcriptional loss, as demonstrated for several tumor suppressor genes as well mismatch repair genes [19-21]. The epigenetic event could be considered to be one of the “hits” in the Knudson’s hypothesis [22]. Methylation of the hMLH1 promoter region has recently been described in many MSI tumors [23-26]. Based on the results that partial methylation of the MLH1 promoter is a common age- related event [27], we have chosen the HpaII restriction assay to detect only the fully methylated samples.