The angiotensin-converting enzyme (ACE) insertion/deletion polymorphism is an independent risk factor for cardiovascular disease. It has also been suggested that some HLA genes may contribute to the genetic susceptibility to essential hypertension. So far, an association between ACE polymorphism and HLA antigens in arterial hypertension has not been reported. We have studied 94 subjects with newly diagnosed essential hypertension, 49 men and 45 women (mean age, 52.3 +/- 11.3 years), as well as 104 randomly selected, age- and gender-matched normotensive individuals (54 men and 50 women, mean age 48.7 +/- 10.8 years). Both cohorts originated from the Greek population and lived in the greater Athens area. The ACE genotype was analyzed by polymerase chain reaction. HLA class I and II antigens were studied by serologic and molecular techniques. The prevalence of the ACE genotypes did not differ significantly between hypertensives and normal individuals. The casual blood pressure levels and the average ambulatory blood pressure levels were similar among the three ACE genotypes. Hypertensives with the ACE-DD genotype were characterized by an increased prevalence of the HLA-A2 antigen (50% v 31.4%, P < .005) and DR6 (16.7% v 11.4%, P < .01) in comparison to the normotensive subjects with the ACE-DD genotype. HLA-A24 was found more frequently among the hypertensives with the ACE-ID genotype than in the normal controls with the same genotype (35.5% v 26.4%, P < .05). ACE-DD genotype is associated with a high prevalence of specific HLA antigens. The coexistence of the ACE-DD genotype with certain HLA phenotypes could reveal a distinct hypertensive population with increased risk for cardiovascular events.