Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine, which is dependent on vitamins (folic acid, B12 and B6) as cofactors or cosubstrates. Severe hyperhomocysteinemia (homocystinuria), due to inherited metabolic defects of Hcy metabolism, is associated with very high risk of venous thromboembolism (VTE); treatment with vitamins is associated with dramatic decrease of VTE risk. Several case-control and prospective studies showed that also mild/moderate hyperhomocysteinemia (which is caused by the interaction of environmental factors with mild genetic abnormalities of Hcy metabolism) is associated with heightened risk of VTE; however, it is uncertain whether treatment with vitamins also decreases the VTE risk in these patients.