BACKGROUND: Prospective studies have identified many markers of systemic inflammation that are powerful predictors of future cardiovascular events. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as a genetic risk factor for cardiovascular disease. In this work, we evaluated the relationship between the levels of inflammation markers and MTHFR genotype among cardiovascular disease free subjects of the ATTICA study. METHODS: During 2001-2002, we randomly enrolled for genetic evaluation 574 subjects from Attica region, Greece. In this work, we investigated demographic, lifestyle, clinical, biochemical and genetic information from 322 men (46+/-13 years) and 252 women (45+/-14 years). Among other characteristics, we measured various inflammatory markers levels in relation to C677T MTHFR genotype distribution. RESULTS: The MTHFR genotypes distribution was: homozygous normal (CC) genotype, 41%; heterozygous (CT), 48%; and homozygous mutant (TT) genotype, 11%. C-reactive protein (CRA), fibrinogen, white blood cell (WBC) counts and amyloid-a levels were higher in TT compared to CC and CT genotypes (p<0.01), in both genders, even after controlling for various potential confounders. CONCLUSION: The observed association between markers of systemic inflammation with MTHFR genotype may state a hypothesis for a common pathobiological mechanism between inflammation process and MTHFR, which is a key enzyme in homocysteine (Hcy) metabolism.