Our study attempted to evaluate the importance of changes in the circulating renin-angiotensin-aldosterone system (RAAS) and in hemodynamics in relation to observed changes in cardiovascular structure. We studied previously untreated men (n = 28) with essential nonmalignant hypertension and a supine casual diastolic blood pressure > 95 mm Hg on three to four separate (> 1-week interval) occasions measured in triplicate. We used intraarterial blood pressure, dye-dilution technique, plethysmography (hands), eye-ground photos, M-mode echocardiography, radio immunoassays, and multiple regression analysis. Patients were randomized to 6 months of double-blind treatment with either enalapril or hydrochlorothiazide, following 4 to 6 weeks on placebo. We found that enalapril blocked the plasma angiotensin converting enzyme (ACE) with a secondary increment in plasma renin activity (PRA) and reductions in angiotensin II (AII) and aldosterone. Blood pressure was lowered through a reduction in total peripheral resistance (TPR). Hydrochlorothiazide increased PRA, AII, and aldosterone, and lowered blood pressure mainly through a reduction in cardiac output. Enalapril was significantly more effective than hydrochlorothiazide in reversing structural changes in the retinal and hand vasculature as well as in the heart. A reduction in cardiac hypertrophy was seen even in the occasional enalapril-treated patient, in whom little or no reduction in blood pressure occurred. In the stepwise regression analyses, the changes in retinal and hand vascular structure were most strongly related to various changes in the RAAS, explaining 15 to 34% of the variance. For the changes in cardiac structure, the type of therapy (enalapril or hydrochlorothiazide) appeared to be the most important factor, explaining between 29 and 50% of the variance. The changes in cardiac structure were even more strongly related to changes in the RAAS for the enalapril treated patients and explained up to 55% of the variance in cardiac structure. It can be concluded that the reversal of structural vascular changes during antihypertensive therapy was more dependent on the blockade of the RAAS than on lowering of the blood pressure.