To determine the effects of the renin-angiotensin-aldosterone system on development of tolerance and fluid retention in patients with chronic congestive heart failure during long-term prazosin treatment, plasma renin concentration, aldosterone, norepinephrine and maximal exercise tolerance were measured during chronic therapy with digitalis and diuretics, to which prazosin, captopril or a combination of both drugs was added. Plasma renin concentration and aldosterone level decreased slightly during prazosin therapy and norepinephrine level increased significantly. When captopril was given, plasma renin concentration increased as expected, aldosterone level normalized and norepinephrine level decreased significantly. When prazosin was added to captopril therapy, norepinephrine level increased and plasma renin concentration and aldosterone level did not change. Exercise capacity did not increase during prazosin treatment, but was increased with captopril treatment. Prazosin treatment was associated with an increase in body weight even though the dose of furosemide was increased. Inhibition of the renin-angiotensin system did not prevent fluid retention induced by prazosin during combination therapy. These findings suggest that the renin-angiotensin-aldosterone system is not substantially involved in development of tolerance and fluid retention during prazosin therapy; stimulation of plasma norepinephrine may be of decisive importance.