Long-term treatment with muzolimine in patients with essential hypertension has provided very interesting results. The administration of the drug caused an immediate significant decrease in blood pressure which was then maintained for as long as 30 months. The fall in blood pressure was initially associated with a significant decrease in body weight, a clear rise in plasma renin activity (PRA) and a significant increase in plasma aldosterone concentration; all these changes are consistent with a depletion of extracellular volume and blood volume. With time, however, the mentioned changes were reversed. Body weight, PRA and plasma aldosterone were normalized after three weeks of treatment and remained normal thereafter. This late observation suggests a normalization in extracellular fluid volume and blood volume, and an antihypertensive effect of the drug independent from volume depletion. How can this effect occur? One possible explanation is a direct vasodilatory effect of muzolimine which has been shown in experimental animals. Against such a possibility is the unsuccessful treatment of hypertension in oliguric patients on regular dialysis treatment. A second possibility is a decrease in sodium content of the arteriolar wall with the consequent decrease in vascular response to pressor agents (angiotensin II, catecholamines). A third possibility is a hemodynamic adjustment to the initial volume depletion which would normalize cardiac output and peripheral resistances (autoregulation) so that normal blood pressure is maintained as in normal subjects.