BACKGROUND & AIMS Detection of tumor-derived DNA alterations in stool is an intriguing new approach with high potential for the noninvasive detection of colorectal cancer (CRC). Because of heterogeneity of tumors, usually multiple markers distributed throughout the human genome need to be analyzed. This is labor intensive and does not allow for high through-put screening. Therefore, markers with high sensitivity and good specificity are needed. We explored the potential of a single epigenetic marker in comparison with fecal occult blood testing (FOBT) for the discrimination of patients with CRCs and adenomas from those without. METHODS Methylation-specific polymerase chain reaction (PCR) was performed to analyze hypermethylated in cancer 1 (HIC1) promoter methylation status in a blinded fashion in stool samples from 26 patients with CRC, 13 with adenoma > or =1 cm, 9 with hyperplastic polyps, 9 with chronic inflammatory bowel disease, and 32 with endoscopically normal colon. RESULTS Ninety-seven percent of the stool samples contained amplifiable DNA. Forty-two percent of the samples from patients with CRC and 31% of the samples from patients with colorectal adenoma > or =1 cm were positive for HIC1 promoter methylation. No methylated HIC1 promoter DNA was detected in the fecal DNA from patients with endoscopically normal colon or hyperplastic polyps. CONCLUSIONS The epigenetic marker HIC1 promoter methylation carries high potential for the remote detection of CRCs. We postulate that a panel of merely a few genetic and epigenetic markers will be required for the highly sensitive and specific detection of CRCs and adenomas in fecal samples from affected patients.