Heat-shock proteins protect cells from damage but are also often the target of immune responses in inflammation and may therefore both induce and perpetuate the chronic inflammation characterizing atherosclerosis. Hypertension is a well-established risk factor for atherosclerosis, and recently, borderline hypertension also has been related to atherosclerosis. The present study investigated the possible role of heat-shock proteins in borderline hypertension and their relation to atherosclerosis by investigating antibody titers against the 65-kD heat-shock protein (HSP65). Sixty-six men with borderline hypertension and 67 age-matched normotensive men (diastolic pressure, 85 to 94 and < 80 mm Hg, respectively) were recruited from a population screening program. Titers of antibodies to HSP65 were determined by enzyme-linked immunosorbent assay. The presence of carotid atherosclerosis was determined by B-mode ultrasonography. Twenty-seven individuals had atherosclerotic plaques; 48 were smokers (more than one to two cigarettes per day). Borderline hypertensive men had higher anti-HSP65 reactivity than normotensive control subjects (P = .034). Smokers with atherosclerosis had low levels of antibodies to HSP65 compared with nonsmokers with atherosclerosis (P = .002). Furthermore, when high-risk individuals (borderline hypertension plus plaque, n = 15) were compared with matched low-risk individuals (normotensive with no plaque, n = 15), the high-risk men had significantly enhanced antibody titers to HSP65 (P = .041). In conclusion, we demonstrate that serum antibody titers to HSP65 are enhanced in individuals with borderline hypertension, which may indicate an ongoing immune reaction in the artery wall. (Hypertension. 1997;29:40-44.)