The administration of atrial natriuretic factor to patients with cirrhosis, and avid sodium retention causes marked hypotension and blunted kidney responses. To evaluate whether the unresponsiveness of the kidney is caused by a fall in mean blood pressure below a critical value for the renal blood perfusion pressure (80 mm Hg), we studied nine such patients and compared the effects of synthetic atrial natriuretic factor alone (1 μg/kg as a bolus) with those of an atrial natriuretic factor combination with infused norepinephrine titrated to raise baseline blood pressure by 15 to 20 mm Hg (182 to 625 ng/kg/min). The administration of atrial natriuretic factor during norepinephrine infusion caused a fall in mean blood pressure to values not less than 80 mm Hg in eight of nine patients, with a slight natriuresis (> 5 μmol/min) in five patients but no changes in the other four. The mean urinary sodium output was markedly lower than that previously observed after atrial natriuretic factor injection into normal subjects and into cirrhotic patients without avid sodium retention. Unlike sodium excretion, urine flow rate and free water clearance (which were not affected by atrial natriuretic factor alone) were markedly improved by the coadministration of norepinephrine and atrial natriuretic factor. In four additional patients we studied the urinary electrolyte excretion during a low-dose infusion of atrial natriuretic factor (20 ng/kg/min) to which an infusion of norepinephrine titrated to maintain blood pressure over 80 mm Hg was added. In only one of these four patients urinary sodium output consistently increased during atrial natriuretic factor infusion, and the output increased even more when norepinephrine was added. These data suggest that the blunted natriuretic activity of atrial natriuretic factor in patients with advanced cirrhosis cannot be offset by preventing the blood pressure from falling below a critical value of 80 mm Hg. Kidney responsiveness to atrial natriuretic factor activity, however, is partly restored by the ability of the peptide plus norepinephrine to stimulate diuresis and free water excretion. (HEPATOLOGY 1992;15:824–829).