Sterol regulatory element binding proteins (SREBPs) are membrane-bound transcription factors that control the metabolism of cholesterol and fatty acids in mammalian cells. We postulated that polymorphisms (SNPs) in SREBP-2 gene might influence lipid parameters and the risk of coronary atherosclerosis. PCR-SSCP analysis and direct sequencing of DNA from 64 asymptomatic hypercholesterolemic men revealed seven genetic SREBP-2 SNPs. The genotype distribution of four of these SNPs (1668G>T, 1784G>C, 3474T>C and 3705C>T), and their influence on plasma lipid values and clinical parameters was studied in 655 asymptomatic men previously selected for the presence of at least one cardiovascular risk factor (hypertension, hypercholesterolemia, tobacco consumption). No significant relation was found with lipid parameters but there was a significant association between the 1784G>C polymorphism and intima-media thickness (IMT) measured in 497 subjects. Thus, a common variation in the SREBP-2 gene is related with early-stage carotid atherosclerosis in subjects with a risk of cardiovascular events without detectable change in plasma lipid levels.