BACKGROUND: The oxidative modification of low-density lipoprotein (LDL) has been suggested to be a key element in atherogenesis, while methylenetetrahydrofolate reductase (MTHFR) C677T mutation has been associated with the development of coronary heart disease. We evaluated whether adoption of a Mediterranean type of diet is associated with oxidized LDL levels, as well as the role of MTHFR C677T mutation in this relationship. METHODS: We studied demographics, lifestyle, clinical, biochemical and genetic data from 322 men (46+/-13 years) and 252 women (45+/-14 years), without any clinical evidence of cardiovascular disease, from the Attica region, Greece (i.e. the ATTICA study). Among the other parameters we also measured oxidized (ox)-LDL levels, and the distribution of MTHFR. Adherence to the Mediterranean diet was evaluated by a special diet score. RESULTS: The distribution of MTHFR genotypes was: 41% for homozygous normal (CC) genotype, 48% for heterozygous (CT) and 11% for homozygous mutant (TT) genotype. Ox-LDL levels were higher in TT as compared to CC and CT (70.8+/-26 vs. 51.0+/-26 vs. 63.7+/-24 mg/dl, p<0.001). Greater adherence to the Mediterranean diet was inversely associated with ox-LDL levels (standardized beta=-0.34, p<0.001), after controlling for several confounding variables; however, stratified analysis revealed that adherence to the Mediterranean diet was associated with lower ox-LDL levels in TT and CT individuals (standardized beta=-0.67, p=0.001 and standardized beta=-0.66, p=0.025, respectively), but not in CC (standardized beta=-0.18, p=0.10), after controlling for several potential confounders. CONCLUSION: The observed gene-to-diet interaction on ox-LDL concentrations may provide a pathophysiological explanation by which a Mediterranean type of diet could influence coronary risk in people with increased oxidative stress.