A genetic polymorphism in position 677 of the MTHFR gene has been often referred as a risk factor for cardiovascular diseases (1). This is principally due to its association with moderately elevated plasma level of homocysteine, an independent risk factor for occlusive arterial disease in the coronary, cerebral and peripheral vessels, and also a risk factor for venous thrombosis. Methylentetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylentetrahydrofolate (CH2-H4 folate) to methyltetrahydrofolate (CH3-H4 folate), the major methyl donor for the conversion of homocysteine to methionine. The C677T mutation is a common polymorphism of the human enzyme, for which 10% of the population is homozygous (2-4). C677T base change leads to the replacement of Ala-222 by valine and it is associated with reduced specific activity and thermolability of MTHFR. Homozygosity for the C677T mutation is the most common genetic cause of mild hyperhomocysteinemia and its pathological consequences. Human plasma samples of 33 subjects carrying the C677T mutation in the MTHFR gene have been analysed by using a proteomic approach, in order to study the whole plasma protein pattern and identify novel markers of pathology in individuals carrying the C677T mutation in the MTHFR gene. Two-dimensional analysis of the plasma protein content of 13 control individuals and 20 mutants allowed the identification of a specific pattern associated to the homozygous mutant genotype (TT). First of all, several proteins mostly related with the coagulation process appeared differently expressed in TT subjects, such as α2-antiplasmin, prothrombin, apolipoprotein A1. Interestingly, we found also a specific differential expression profile associated to the mutant TT genotype. In fact, a protein spot shifted to a more basic isoelectric point was observed in mutants 2D-maps. Mass spectrometry identification revealed the spot corresponded to vitamin D binding protein (DBP or Gc globulin). A different allelic variant of the same protein was present in normal individuals. DBP is a very interesting multi-functional plasma protein. Besides the binding of vitamin D and its derivatives, one of DBP more interesting roles is its involvement in extracellular actin scavenger system (5). This function and, in particular, the affinity for actin, could be related to the presence of different allelic variant of DBP and to the risk for cardiovascular diseases development. In fact, in presence of an impaired actin scavenging system, monomeric actin would polymerize into filament form, potentially able to block and damage the microvasculature.