Autoimmune mechanisms have been proposed to play a role in the pathogenesis of primary (essential) hypertension. Autoantibodies against the α₁-adrenergic receptor have been described in patients with malignant and secondary hypertension. To investigate the incidence of autoantibodies against the α₁-adrenoceptor in patients with primary hypertension, we examined the immunoglobulin fractions of sera from 54 patients with primary hypertension and 26 normotensive control subjects for the presence of autoantibodies against the α₁-adrenoceptor. Sera from 24 patients (44%) and 3 subjects (12%) were positive. An epitope analysis of 16 autoantibody-positive immunoglobulin fractions revealed that in two thirds of the cases, the antibodies were directed against the first extracellular loop of the α₁-adrenoceptor and in one third, against the second. The autoantibodies had a positive chronotropic effect on isolated neonatal rat cardiomyocytes, an effect that was blocked by α₁-adrenergic antagonists. Since the functional characteristics of the autoantibodies showed no desensitization phenomena, they may play a role in elevating peripheral vascular resistance and promoting cardiac hypertrophy in patients with primary hypertension.