A distinctive pathway of colorectal carcinogenesis termed CpG island methylator phenotype is characterized by extensive DNA methylation in colorectal carcinoma (CRC) cells but not in nonneoplastic mucosa. Many CRCs with CpG island methylator phenotype have methylation of the hMLH1 mismatch repair gene and consequently have high levels of microsatellite instability (MSI-H). MSI-H confers distinctive clinical-pathologic features, but the phenotype of microsatellite-stable CRC with methylation has not been characterized in detail. We therefore examined the clinical-pathologic features of 87 sporadic microsatellite-stable CRCs that had been characterized for methylation of p16, p14, MGMT, hMLH1, MINT1, MINT2, and MINT31. Regression analyses of each clinical-pathologic characteristic were run against the individual and aggregated methylation markers to evaluate and quantify associations. CpG island methylation was associated with right-sided carcinoma (odds ratio = 6.9, P = 0.03). Paucity of gland formation, indicating poor differentiation, was strongly associated with methylation (beta = -42.6, P = 0.0008), as were presence of cribriform glands (beta = 34.3, P = 0.02) and lack of corkscrew/serrated glandular pattern (beta = -32.5, P = 0.03). Our epigenotype-phenotype correlation study shows that microsatellite-stable CRC with CpG island methylation have a distinctive pathologic phenotype with both similarities to and differences from MSI-H tumors.