Epigenetic marks are extensively altered in cancer but may also change in normal tissues with age, which is the primary risk factor for most cancers. We conducted an epigenome-wide study to identify age-related methylation sites and examine their relationship to cancer and other underlying epigenetic marks. We analyzed 1006 blood DNA samples of women aged 35-76 years from the Sister Study and found that 7694 (28%) of the 27 578 CpGs assayed were associated with age (false discovery rate, q < 0.05). Using independent data sets, we confirmed 749 'high-confidence' age-related CpG (arCpGs) sites in normal blood. Based on The Cancer Genome Atlas data, we show that these age-related changes are largely concordant in a broad variety of normal tissues and that a significantly higher (71-91%, P < 10(-74)) than expected proportion of increasingly methylated arCpGs (IM-arCpGs) were overmethylated in a wide variety of tumor types. IM-arCpGs sites occurred almost exclusively at CpG islands and were disproportionately marked with the repressive H3K27me3 histone modification (P < 1 × 10(-) (50)). Genes containing these IM-arCpG sites were highly enriched for developmental and signaling pathways (P < 10(-) (10)). Our findings suggest that as cells acquire methylation at age-related sites, they have a lower threshold for malignant transformation that may explain in part the increase in cancer incidence with age.