DNA methylation is a reversible epigenetic phenomenon that can be modified by nutrients such as folate and influenced by the MTHFR677C>T polymorphism in a gene-nutrient interaction manner. In human cancer, global DNA hypomethylation is an almost universal finding.Cancer subjects had lower plasma folate concentrations (P=0.003), higher frequency of MTHFR677TT (P=0.013) and lower PBMCs-DNA methylation than controls (P<0.0001). A DNA methylation threshold of 4.74% categorized cancer patients from controls. Subjects with cancer at follow-up had at enrollment lower DNA methylation than controls (P<0.0001). The association of MTHFR677TT and low plasma folate showed the lowest DNA methylation levels (4.39%). Cancer deaths had a lower DNA methylation compared with other cause deaths (P=0.015) and the survivors had an increased DNA methylation compared to cancer (P=0.004). Low global DNA methylation in PBMCs may be a useful predictive biomarker of cancer.