Although heat shock proteins (Hsp's) are present in the sera of healthy individuals and at elevated levels in subjects with early cardiovascular disease, their physiologic role in and value for predicting the development and/or progression of atherosclerosis have not been evaluated. Serum was obtained from 218 subjects with established hypertension (diastolic pressure >95 mm Hg) before their enrollment in the European Lacidipine Study on Atherosclerosis. Hsp60 and Hsp70, and anti-human Hsp60, anti-human Hsp70, and anti-mycobacterial Hsp65 antibody levels were measured by enzyme immunoassay. As an indicator of the presence/progression of atherosclerosis, the means of the maximum intima-media (I-M) thicknesses in the far walls of common carotid arteries and bifurcations (CBMmax) were determined by ultrasonography at the time of enrollment and 4 years afterward. Increases in I-M thicknesses at follow-up were less prevalent in subjects having high serum Hsp70 levels (75th percentile) at the time of enrollment (odds ratio, 0.42; 95% confidence interval [CI], 0.22 to 0.8, P=0.008). Although a similar trend was observed for serum Hsp60 levels, this was not statistically significant (odds ratio, 0.6; 95% CI, 0.32 to 1.11, P=0.10). There was no relation between anti-Hsp antibody levels and changes in I-M thicknesses. The relation between Hsp70 levels and changes in I-M thickness was independent of age, atenolol or lacidipine treatment, smoking habits, and blood lipid levels. These findings indicate that circulating Hsp70 levels predict the development of atherosclerosis in subjects with established hypertension, and an intriguing possibility is that Hsp70 protects against or modifies the progression of atherosclerosis in this subject group.