Nutrient-gene interactions within one-carbon metabolism modulate DNA methylation, the major potentially reversible epigenetic modification in eukaryotic cells. The cytosolic serine hydroxymethyltransferase (SHMT1) regulates the metabolic balance between nucleotide synthesis and methylation in one-carbon pathway. The SHMT1-1420T allele has been associated with a reduced enzyme activity and a decreased risk of cancer. By enhancing SHMT1 expression, ferritin affects folate-mediated one-carbon metabolism. Aim of this study was to analyze how the interaction among ferritin, folate and SHMT1-1420C>T polymorphism may affect peripheral blood mononuclear cells (PBMCs) DNA methylation (LC/ESI/MS method) in 537 subjects enrolled in the Verona Heart Studyto identify a possible biomarker for cancer. Results showed that SHMT1-TT carriers, under a high ferritin/low folate condition, show significantly increased PBMCs genomic DNA methylation than SHMT1-CC subjects (P=0.01). Since cancer is usually associated with genomic hypomethylation, the increased genomic methylation in SHMT1-1420TT genotypes in presence of high ferritin/low folate, could be potentially protective for cancer risk.