Circulatory observations have been made on six normal subjects and six hypertensive patients before and after the acute intravenous injection of 5 mg. of phentolamine.The drug caused a prompt reduction in systemic vascular resistance which resulted in a rapid fall in systemic blood pressure in spite of an increase in heart rate and cardiac output.Evidence is presented that the predominant vascular activity of the drug is to cause a direct relaxation of vascular smooth muscle, an effect far more potent than its antagonism of circulating catecholamines or its very much weaker sympathetic-blocking action. This direct depressor effect on vascular smooth muscle unaccompanied by any but slight sympathetic blocking activities endows the drug with theoretically ideal antihypertensive properties.Phentolamine caused a transient but significant reduction in oxygen uptake in the majority of individuals. It is suggested that this may be due to a direct inhibition of cellular oxidative mechanisms.An appraisal of the circulatory activities of the drug with particular regard to its use as a diagnostic test for pheochromocytoma leads to serious doubts, not only with regard to the precision with which the results of such tests can be interpreted, but also to the validity of the use of the drug as a reliable screening test for excessive circulating catecholamines.