Methylation of promoter CpG islands in colorectal cancer (CRC) falls into two categories: age related and cancer specific. Most cancer-specific methylation at CpG islands occurs in a subset of cases that display the CpG island methylator phenotype (CIMP). The underlying cause of CIMP is not known. Using methylation-specific PCR, we studied 47 CRC patients for methylation at five loci to determine whether the methylation status of CpG islands is associated with family history of cancer. Four of the loci were differentially methylated between the CRC cases with a family history and those with no family history. Patients with methylation at all four loci were 14 times more likely to have a family history of cancer than patients with methylation at none of the four loci. These findings suggest that there may be a genetic component to CIMP in CRC.