HSPA1A is a serum and intracellular heat shock protein with antiapoptotic and antithrombotic properties. The present study examines the hypothesis that a decrease in the synthesis of this protein in relation to certain polymorphisms of the regulatory region of the HSPA1A gene can define a vascular disease risk phenotype. A randomly selected population was studied and stratified into groups according to the degree of vascular risk. After applying the Task Force Chart to 452 people, the subjects were divided into three groups: group 0 (no vascular risk factor or risk < 5%), n = 239; group 1 (moderate (10-20%) risk, with no clinical cardiovascular disease), n = 161; and group 2 (overt atherosclerosis), n = 52. Serum and intragranulocytic HSPA1A was quantified, and direct Sanger sequencing was performed in all subjects. An analysis was made of the association of two single nucleotide polymorphisms (db rs1008438 -110A/C and db rs1043618 +190 G/C) with circulating and intragranulocytic HSPA1A and the risk of atherosclerosis. The atherosclerotic subjects showed significantly lower circulating HSPA1A levels than the other groups, regardless of the genotype. The patients with CC genotype for both polymorphisms showed significantly lower intragranulocytic HSPA1A levels than the other genotypes. Serum HSPA1A concentrations could be proposed as a biomarker of cardiovascular disease. CC homozygosis for polymorphisms db rs1008438 and db rs1043618 is associated with a decrease in the intragranulocytic production of HSPA1A. Given the antiatherogenic functions of intracellular HSPA1A, the -110A and +190 G alleles could constitute potential genetic biomarkers of a less severe clinical phenotype for the risk of developing atherosclerosis.